latest research for prostate cancer

Prostate Cancer Research Results and Study Updates

See Advances in Prostate Cancer Research for an overview of recent findings and progress, plus ongoing projects supported by NCI.

Under a new FDA approval, enzalutamide (Xtandi) can now be used alone, or in combination with leuprolide, to treat people with nonmetastatic prostate cancer that is at high risk of returning after surgery or radiation.

FDA approved enzalutamide (Xtandi) combined with talazoparib (Talzenna) for metastatic castration-resistant prostate cancer with alterations in any of 12 DNA repair genes. The drug combination, which blocks both DNA repair activities and hormones that fuel cancer growth, was more effective than the standard treatment in a large clinical trial.

The Decipher genomic test found high-risk prostate cancer even when conventional tests said the tumors were lower risk. This discrepancy appeared to happen more frequently for African-American men.

Men diagnosed with low-risk prostate cancer are increasingly opting against immediate treatment and choosing active surveillance instead, a new study finds. In fact, rates of active surveillance more than doubled between 2014 and 2021.

Adding darolutamide (Nubeqa) to ADT and docetaxel (Taxotere) can improve how long men with hormone-sensitive metastatic prostate cancer live without causing more side effects, results from the ARASENS trial show.

Many with prostate cancer can safely receive shorter, higher-dose radiation therapy after surgery, a new study has found. The approach, called HYPORT, didn’t harm patients’ quality of life compared with the standard radiation approach, trial finds.

A drug called Lu177-PSMA-617 may be a new option for treating advanced prostate cancer. In a large clinical trial, adding the drug—a type of radiopharmaceutical—to standard treatments improved how long participants lived.

For some men with prostate cancer, a genetic biomarker test called Decipher may help predict if their cancer will spread elsewhere in the body. The test could help determine whether hormone therapy, which can cause distressing side effects, is needed.

FDA’s recent approval of relugolix (Orgovyx) is expected to affect the treatment of men with advanced prostate cancer. A large clinical trial showed that relugolix was more effective at reducing testosterone levels than another common treatment.

FDA has approved olaparib (Lynparza) and rucaparib (Rubraca) to treat some men with metastatic prostate cancer. The PARP inhibitors are approved for men whose cancers have stopped responding to hormone treatment and have specific genetic alterations.

For some men with prostate cancer at high risk of spreading, a large clinical trial shows an imaging method called PSMA PET-CT is more likely to detect metastatic tumors than the standard imaging approach used in many countries.

Testing for prostate cancer with a combined biopsy method led to more accurate diagnosis and prediction of the course of the disease in an NCI study. The method is poised to reduce the risk of prostate cancer overtreatment and undertreatment.

In the Veterans Affairs health care system—where all patients have equal access to care—African American men did not appear to have more-aggressive prostate cancer when diagnosed or a higher death rate from the disease than non-Hispanic white men.

In two large clinical trials, the drugs enzalutamide (Xtandi) and apalutamide (Erleada), respectively, combined with the androgen deprivation therapy, improved the survival of men with metastatic prostate cancer that still responds to hormone-suppressing therapies.

The Prostate Cancer Prevention Trial showed that finasteride can reduce the risk of prostate cancer, but might increase the risk of aggressive disease. NCI’s Howard Parnes talks about subsequent findings and what they mean for men aged 55 and older.

The investigational drug darolutamide can help delay the spread of prostate cancer in some men with the disease, a recent clinical trial shows. In addition, the drug caused fewer side effects than similar prostate cancer drugs.

For African American men, the risk of dying from low-grade prostate cancer is double that of men of other races, a new study has found. But, despite the increase, the risk is still small.

Researchers have found that men with advanced prostate cancer may be more likely than previously thought to develop a more aggressive form of the disease. The subtype, called t-SCNC, was linked with shorter survival than other subtypes.

RESPOND is the largest coordinated study on biological and non-biological factors associated with aggressive prostate cancer in African-American men. The study is an effort to learn why these men disproportionally experience aggressive disease.

In a small clinical trial, researchers compared the efficacy of a much lower dose of the cancer drug abiraterone (Zytiga) taken with a low-fat breakfast with a full dose taken on an empty stomach, as directed on the drug’s label.

In the trial that led to the approval, apalutamide (Erleada) delayed cancer metastasis for men with prostate cancer that is resistant to androgen deprivation therapy.

A new study in mice has revealed a molecular link between a high-fat diet and the growth and spread of prostate cancer. The findings, the study leaders believe, raise the possibility that changes in diet could potentially improve treatment outcomes in some men.

The Food and Drug Administration (FDA) has expanded the approval of abiraterone (Zytiga®) for men with prostate cancer. The agency approved abiraterone, in combination with the steroid prednisone, for men with metastatic prostate cancer that is responsive to hormone-blocking treatments (also known as castration-sensitive) and is at high risk of progressing.

Researchers have identified an emerging subtype of metastatic prostate cancer that is resistant to therapies that block hormones that fuel the disease.

In two large clinical trials, adding the hormone-blocking drug abiraterone to androgen-deprivation therapy (ADT) allowed men with metastatic hormone-sensitive prostate cancer to live longer than men who were treated with ADT alone.

Findings from a new study show testing for two biomarkers in urine may help some men avoid an unnecessary biopsy to detect a suspected prostate cancer.

Long-term results from an NCI-sponsored clinical trial suggest that adding androgen deprivation therapy to radiation therapy can improve survival for some men with recurrent prostate cancer.

Researchers estimate that nearly 12% of men with advanced prostate cancer have inherited mutations in genes that play a role in repairing damaged DNA.

Researchers have identified a potential alternative approach to blocking a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List

Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches

Mamello sekhoacha.

1 Department of Pharmacology, University of the Free State, Bloemfontein 9300, South Africa

Keamogetswe Riet

2 Department of Health Sciences, Central University of Technology, Bloemfontein 9300, South Africa

Paballo Motloung

Lemohang gumenku, ayodeji adegoke.

3 Cancer Research and Molecular Biology Laboratories, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan 200005, Nigeria

Samson Mashele

Associated data.

Information was available in the public domain. Databases have been provided in Section 2 .

Simple Summary

Prostate cancer affects men of all racial and ethnic groups and leads to higher rates of mortality in those belonging to a lower socioeconomic status due to late detection of the disease. There is growing evidence that suggests the contribution of an individual’s genetic profile to prostate cancer. Currently used prostate cancer treatments have serious adverse effects; therefore, new research is focusing on alternative treatment options such as the use of genetic biomarkers for targeted gene therapy, nanotechnology for controlled targeted treatment, and further exploring medicinal plants for new anticancer agents. In this review, we describe the recent advances in prostate cancer research.

Prostate cancer is one of the malignancies that affects men and significantly contributes to increased mortality rates in men globally. Patients affected with prostate cancer present with either a localized or advanced disease. In this review, we aim to provide a holistic overview of prostate cancer, including the diagnosis of the disease, mutations leading to the onset and progression of the disease, and treatment options. Prostate cancer diagnoses include a digital rectal examination, prostate-specific antigen analysis, and prostate biopsies. Mutations in certain genes are linked to the onset, progression, and metastasis of the cancer. Treatment for localized prostate cancer encompasses active surveillance, ablative radiotherapy, and radical prostatectomy. Men who relapse or present metastatic prostate cancer receive androgen deprivation therapy (ADT), salvage radiotherapy, and chemotherapy. Currently, available treatment options are more effective when used as combination therapy; however, despite available treatment options, prostate cancer remains to be incurable. There has been ongoing research on finding and identifying other treatment approaches such as the use of traditional medicine, the application of nanotechnologies, and gene therapy to combat prostate cancer, drug resistance, as well as to reduce the adverse effects that come with current treatment options. In this article, we summarize the genes involved in prostate cancer, available treatment options, and current research on alternative treatment options.

1. Introduction

Prostate cancer affects middle-aged men between the ages of 45 and 60 and is the highest cause of cancer-associated mortalities in Western countries [ 1 ]. Many men with prostate cancer are diagnosed by prostate biopsy and analysis, prostate-specific antigen (PSA) testing, digital rectal examination, magnetic resonance imaging (MRI), or health screening. The risk factors related to prostate cancer include family risk, ethnicity, age, obesity, and other environmental factors. Prostate cancer is a heterogeneous disease both on the basis of epidemiology and genetics. The interplay among genetics, environmental influences, and social influences causes race-specific prostate cancer survival rate estimates to decrease, and thus, results in differences observed in the epidemiology of prostate cancer in different countries [ 2 ]. There is documented proof of a genetic contribution to prostate cancer. Hereditary prostate cancer and a genetic component predisposition to prostate cancer have been studied for years. One of the most predisposing genetic risk factors for prostate cancer is family inheritance. Twin studies and epidemiological studies have both proven the role of hereditary prostate cancer [ 3 ]. Many researchers have looked into the possible role of genetic variation in androgen biosynthesis and metabolism, as well as the role of androgens [ 4 , 5 ]. Genomics research has identified molecular processes that result in certain cancer developments, such as chromosomal rearrangements [ 2 ].

In general, gene mutations are a prevalent cause of cancer. Candidate genes for prostate cancer predisposition are genes that partake in the androgen pathway and metabolism of testosterone. The development of prostate epithelium and prostate cancer cells relies on the androgen receptor signaling pathway and testosterone [ 6 ]. The identification of cancer biomarkers and targeting of specific genetic mutations can be used for targeted treatment of prostate cancer. Biomarkers that can be used for targeted treatment are DNA tumor biomarkers, DNA biomarkers, and general biomarkers [ 7 ].

Prostate cancer can either be classified as androgen sensitive or androgen insensitive, which is an indicator of testosterone stimulation and the possible treatment option [ 8 ]. Treatment options available for prostate cancer are active surveillance, chemotherapy, radiation therapy, hormonal therapy, surgery, and cryotherapy. Treatment options delivered to a patient depend on the nature of the tumor, PSA level, grade and stage, and possible recurrence. For example, radical prostatectomy, a surgical option that involves the removal of the prostate and nearby tissues, is used in conjunction with radiation therapy for the treatment of low-risk prostate cancer [ 9 ]. For treating cancers that have spread beyond the prostate and have reoccurred, androgen-deprivation therapy, also called hormonal therapy, is recommended [ 1 ]. Each treatment is associated with severe side effects such as toxicity and reduced white and red blood cell counts, which lead to fatigue, hair loss, peripheral neuropathy, erectile incontinence and dysfunction, metastasis, and lastly, developing resistance to the initial treatment. Available treatment options are expensive and pose severe side effects. The discovery of new cost-effective chemotherapeutic agents with little or no side effects and higher efficacy is necessary [ 3 ]. In this review, we provide a holistic overview of prostate cancer, including the diagnosis of the disease, genes and mutations leading to the onset and progression of the disease, treatment options, and alternative treatment options.

2. Materials and Methods

In order to carry out the current review, in 2020, our team began to collect information and carry out a comprehensive search from different databases, i.e., Google Scholar, Pubmed, Springer, Elsevier ScienceDirect, and Web of Science, for studies published from 2010 to 2022, and older studies published as early as 2000 were included in this paper due to relevancy. The articles selected only utilized English texts, and searches were carried out for the following keywords and headings: ”prostate cancer”, ”prostate cancer genetics”, ”prostate cancer diagnosis and treatment”, ’ cancer statistics”, ”the prostate”, ”medicinal plants in prostate cancer treatment”, “traditional medicine”, “alternative therapy for prostate cancer”, ”nanomedicine in prostate cancer”, ”next generation sequencing”, “bioactive compounds in prostate cancer”, and ”drug repurposing in cancer”. Duplicate papers were eliminated, the data were screened, irrelevant works were factored out, and then full-text documents were screened. The inclusion criteria included several factors which involved original articles or review papers. The criteria for exclusion included articles with inadequate and irrelevant information and those without access to full text articles.

2.1. Epidemiology of Prostate Cancer

2.1.1. global scale.

Prostate cancer is one of the most common malignancies in men worldwide [ 10 ]. In 2018, GLOBOCAN reported approximately 1,276,106 new cases of prostate cancer resulting in about 358,989 deaths worldwide, with a higher prevalence in developed countries. On average, 190,000 new prostate cancer cases arise each year, with about 80,000 deaths occurring annually around the world [ 11 ]. The worldwide incidence of prostate cancer differs among various geographical regions and ethnic groups. Black men have the most reported incidence rates of prostate cancer in the world [ 12 ]. The incidence rates of Black Americans are approximately 60% higher than those of white men in America. The highest recorded incidence rates of prostate cancer are seen in developed countries where there is prostate cancer awareness and where prostate-specific antigen (PSA) testing is a prevalent screening practice [ 13 ]. The GLOBOCAN reports of PSA tests indicated high incidence rates in Australasia (111.6 per 100,000) and the USA (97.2 per 100,000) in the year 2012 [ 14 ]. Globally, prostate cancer is predicted to increase to approximately 1.7 million new cases and 499,000 deaths by the year 2030 because of the exponentially growing population and the large population of men who will be 65 years and older [ 15 ].

2.1.2. Local Scale

Little is known about prostate cancer in African countries. Prostate cancer screening using the PSA test or digital rectal examination is not a well-established practice in Africa. There is a higher incidence rate of prostate cancer among men in Southern Africa as compared with Northern Africa [ 16 ]. In South Africa, prostate cancer is one of the most diagnosed cancers in men across the country. As recorded by the South African National Cancer Registry, the incidence rate of prostate cancer in 2007 was 29.4 per 100,000 men. In 2012, the incidence increased to 67.9 per 100,000 men [ 15 ].

2.2. Screening and Diagnosis of Prostate Cancer

Prostate cancer diagnoses at mature stages of the disease and failure of therapy are the main factors leading to an increased mortality rate. There is no single, specific test for prostate cancer; however, it has conventionally been diagnosed by a digital rectal examination (DRE), where a gloved finger is inserted into the patient’s rectum to assess the size of the prostate gland and any abnormalities. However, the prostate-specific antigen (PSA) test remains to be the keystone for prostate cancer screening [ 17 ]. PSA is a glycoprotein secreted by the epithelial cells of the prostate gland. It is usually found in semen, but can also be found in the bloodstream [ 18 ]. During PSA testing, blood samples are taken to test the level of PSA. Then, the blood samples are analyzed at a PSA cut-off point of 4 ng/mL. PSA levels above 4 ng/mL suggest that the patient needs further testing [ 19 ]. Patients with PSA levels between 4 ng/mL and 10 ng/mL have an approximately one in four chance of having prostate cancer. If the PSA is more than 10 ng/mL the possibility of having prostate cancer is over 50% [ 20 ]. PSA is prostate gland specific and not prostate cancer specific; therefore, prostate-specific antigen levels can indicate benign pathologies such as benign prostatic hyperplasia (BPH) and prostatitis and not prostate cancer, and men who do not have prostate cancer have also been reported to have elevated PSA levels. A prostate tissue biopsy is usually performed to confirm the presence of cancer [ 21 ].

A biopsy is a medical procedure in which a thin hollow needle is used to collect small tissue samples from the prostate gland to be observed under a microscope. The biopsy can be performed through the skin between the anus and scrotum or through the rectal wall (known as a transrectal biopsy) [ 22 ]. During a biopsy, the prostate gland is usually located with devices such as magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS). An MRI scanner creates detailed images of body tissue using a strong magnetic field and radio waves [ 23 ]. MRI positive results can be used for specifically targeting abnormal areas of the prostate gland during a biopsy [ 24 ]. A multiparametric MRI can also be a triage test performed without a biopsy if the results were negative for DRE, PSA test, and MRI. A TRUS is a small probe that is deposited into the rectum of a patient. The probe emits sound waves that go through the prostate gland and produce echoes. The probe then recognizes and reads the echoes, and a computer system turns them into a black and white image of the organ [ 25 ].

Biopsy analysis is one of the most reliable methods of prostate cancer diagnosis. Tissue samples of a biopsy are studied and analyzed in the laboratory using a microscope. The cells can also be analyzed to determine how quickly cancer will spread. The biopsy results are usually reported as follows:

• Negative for prostate cancer, there were no cancer cells detected in the biopsy samples.
• Positive for prostate cancer, there were cancer cells detected in the biopsy samples.
• Suspicious, abnormal cells present, but may not be cancer cells [ 26 ].

However, artificial intelligence (AI) and machine learning algorithms have recently advanced, resulting in new classifications for prostate cancer. In recent years, the availability of novel molecular markers, as well as the introduction of advanced imaging techniques such as multiparametric magnetic resonance imaging (mpMRI) and prostate-specific membrane antigen positron emission tomography (PSMA-PET) scans have shifted the paradigm of prostate cancer screening, diagnosis, and treatment to a more individualized approach [ 27 ]. According to the most recent guidelines, any man at risk of prostate cancer should have an MRI of the prostate performed before obtaining a prostate biopsy [ 28 ]. This serves to minimize complications such as lower urinary tract symptoms, hematuria, and temporary erectile dysfunction. Furthermore, the number of biopsy cores obtained is linked to a higher risk of complications such as rectal bleeding, hematospermia, bleeding problems, and acute urine retention [ 29 ]. Therefore, radiomics can help with prostate volume selection and segmentation; prostate cancer (PCa) screening, detection, and classification; and risk stratification, treatment, and prognosis ( Table 1 ).

Benefits and drawbacks of radiogenomics as compared with actual prostate cancer peril stratification management [ 30 ].

2.3. Prostate Cancer and Genetics

Genetic inheritance.

Close family lineage is the primary risk factor for prostate cancer. Men with close relatives diagnosed with prostate cancer are at a 50% risk of developing cancer as compared with men with no family history of prostate cancer [ 26 ]. First-degree relatives with successive generations of diagnosed prostate cancer usually have early onset prostate cancer [ 31 ]. Epidemiologic studies have shown the inheritance of prostate cancer susceptibility genes. Analyses of case-control, twin, and family studies have concluded that prostate cancer risk may be a result of heritable factors. Research has shown specific gene mutations in hereditary prostate cancer and has reported that patients with these mutations have an increased risk of the disease [ 4 ]. In the genetic evaluation of inheritance, scientists use multigene sequencing of men diagnosed with prostate cancer, as well as men at high risk of developing cancer. About 5.5% of these men had detectable mutations in DNA repair genes such as ATM , BRCA1 , and BRCA2 genes. African men have certain genetic mutations that predispose them to prostate cancer; therefore, race and environmental conditions such as migration and food diets are considered to be contributing factors [ 21 ].

Cancer occurs because of changes in the DNA sequence due to mutations such as point mutations, single nucleotide polymorphisms (SNPs), and somatic copy number alterations (SCNAs) [ 31 ]. Mutations can cause prostate cells to become cancerous by turning off tumor suppressor genes and turning on oncogenes [ 32 ]. This often leads to uncontrolled cell division. Mutations in genes can be passed on from generation to generation or be acquired by an individual. Acquired mutations usually occur during DNA replication in the nucleus [ 33 ]. The common genes used as biomarkers for prostate cancer are BRCA genes, HOX genes, the ATM gene, RNase L (HPC1, lq22), MSR1 (8p), and ELAC2/HPC2 (17p11). Table 2 shows most of the genes used as biomarkers for prostate cancer.

Prostate cancer genes used as biomarkers for the disease.

Biomarkers show the advantages of being used for diagnostic procedures, staging, assessing the aggressiveness of the disease, and evaluating the therapeutic process. Multiple advances have been achieved through profiling technologies, including novel biomarkers that guide diagnosis and precision medicine. Modern biological markers, such as the prostate health index (PHI), the TMPRSS2-ERG fusion gene, 4K tests, and PCA3, have proven to increase PSA specificity and sensitivity, resulting in patients avoiding biopsies and reducing over diagnosis [ 76 ]. Table 3 below shows different diagnostic biomarkers and their different tests and categories.

Examples of other diagnostic biomarkers classified as serum-based, urine-based, and tissue-based biomarkers used for prostate cancer [ 77 ].

Figure 1 depicts the developmental stages of prostate cancer [ 78 ].

A schematic depicting the development of prostate cancer. The stages of the cancer onset and progression are indicated by the molecular processes, genes, and signaling pathways which are important in different stages of cancer. The first sign of prostate cancer is an inflammation of the prostate gland as a result of uncontrollable cell division. This uncontrollable cell division is caused by mutations that arise due to damaged DNA. At a chromosomal level, the initiation of prostate cancer begins with the shortening of telomerase at the end of the chromosome. Oxidative stress from prostate gland inflammation can shorten prostatic telomeres [ 78 ]. Research on the Nkx3.1 homeobox gene has shown the impact of the gene on the prostate cancer initiation phase in mice. No tumor suppressor gene has been solely given a role in prostate cancer initiation or progression. However, several genes such as MYC , PTEN , NKX3.1 ., and TMPRSS2-ERG gene fusions are implicated in prostate cancer initiation. TMPRSS2-ERG gene fusions are responsible for the main molecular subtype of prostate cancer. The gene fusion activates the ERG oncogenic pathway, which contributes to the development of the disease. Metastasis of prostate cancer is conserved by the reactivation of pathways involved in cell division, which results in uncontrolled cell division and cell proliferation, leading to metastasis of the cancer [ 79 ]. Gene expression profiling results have indicated an overexpression in EZH2 mRNA and proteins present in metastatic prostate cancer. Due to the functions of EZH2 involving apoptosis and proliferation, EZH2 is a novel target for prostate cancer [ 80 ].

2.4. Precision Medicine for Prostate Cancer

Precision medicine is an emerging field that represents an alternative method, for some men with advanced cancer, to find gene-specific treatment for prostate cancer. It uses genetics as well as environmental biomarkers to determine diagnoses, prognosis therapeutic options for patients, and accurate dosing. Precision medicine classifies diseases using genome sequencing to identify patients who have tumors exhibiting actionable targets and promoting more informed and accurate treatment decisions [ 81 ]. Mutations in prostate cancer-related genes BRCA1 and BRCA2 render men with mCRPC suitable for treatment with either rucaparib or olaparib, and other prostate cancer genes that have responded well to olaparib treatment, which include ATM , CDK12 , CHECK2 , CHECK1 , PALB2 , PP2R2A, and RAD54L [ 82 ]. The influence of BRCA mutations on therapeutic outcomes in a study of 1302 patients with 67 BRCA mutation carriers was investigated. The results showed that patients who received prostatectomy or radiotherapy developed metastasis and had shorter survival as compared with patients who did not have mutations of the BRCA gene. This study also found that the BRCA1 gene was 12% more common than the BRCA2 gene, which was only 2% common. In a recent study, conducted in 2019, the mutation in the BRCA gene (c.4211C > G) was identified in a Chinese patient treated with radiotherapy and ADT for prostate cancer. The study indicated that prostate cancer patients with this specific mutation were sensitive to ADT as well as radiotherapy, making the treatment more effective [ 83 ]. Mutations that make it difficult to treat or design effective CRPC include the F876L mutation, which changes the binding ligand pocket in the AR. Similarly, the W741L/C mutation stimulates specific AR binding that is able to move AR into its active conformation. Such mutations create obstacles to designing effective treatment for CRPC [ 84 ].

2.5. Treatment and Management of Prostate Cancer

The prognostic factors consisting of initial PSA level, clinical TNM stage, and Gleason’s score have been considered together with other factors such as baseline urinary function, comorbidities, and age as a choice of treatment for prostate cancer [ 85 ]. Advances in prostate cancer diagnosis and treatment have enhanced clinicians’ capacities to classify patients by risk and propose therapy based on cancer prognosis and patient preference [ 86 ]. Surveillance, prostatectomy, and radiotherapy are recognized as the standard treatments for stage I–III prostate cancer patients. Androgen ablation by surgical or pharmacological castration can bring about lasting remission in all stage IV and high-risk stage III patients. In this case, first-generation antiandrogens such as flutamide and bicalutamide can aid. However, in stage IV, castration resistance, which is characterized by genomic mutations in the androgen receptor, invariably occurs, and the prognosis is poor [ 87 ]. Table 4 below summarizes prostate cancer treatment options and their adverse effects.

Common prostate cancer treatment options and potential adverse effects [ 88 ].

2.5.1. Active Surveillance

Active surveillance is a structured program that employs monitoring and expected intervention as the main techniques in the management of prostate cancer [ 89 ]. For patients who have low-risk cancers or those who have a short life expectancy, active surveillance has been recognized as the best option. The criteria for active surveillance have recommendations that are usually based on the following factors: disease characteristics, health conditions, life expectancy, side effects, and patient preference [ 90 ]. The PSA level, clinical progression, or histologic progression are used as prostate cancer trigger points [ 91 ].

The advantages of active surveillance are the preservation of erectile function, decreased costs of treatment, avoidance of needless treatment of inactive cancers, and sustaining life quality and normal activities. Its disadvantages include the likelihood of cancer metastasis before treatment, missed opportunity for a remedy, need for a complex therapy with side effects for larger and aggressive cancers, reduced chances of potency preservation mostly after surgery, chances of increased anxiety by patients, and frequent medical checks [ 92 ].

2.5.2. Radical Prostatectomy

Radical prostatectomy is the procedure of medically removing the prostate gland by open and/or laparoscopic surgery [ 93 ]. The procedure requires making small incisions on the abdomen or via the perineum.

Salvage radical prostatectomy is usually recommended to patients with local recurrence in the absence of metastases after undergoing external beam radiation therapy, brachytherapy, or cryotherapy. This may, however, lead to increased morbidity. Patients younger than age 70 with organ-confined prostate cancer, with a life expectancy higher than 10 years who have little to no comorbidities, are best suited for radical prostatectomy. However, there are a few complications associated with its use. These complications include incontinence and erectile dysfunction arising from surgical damage to the urinary sphincter and erectile nerves [ 94 ].

2.5.3. Cryotherapy

This method involves the use of surgical insertion of cryoprobes into the prostate under ultrasound guidance. It involves freezing of the prostate gland to a temperature from −100 °C to −200 °C for about 10 min. However, there are reports of complications associated with the use of this method, including urinary incontinence and urinary retention, erectile dysfunction, fistula, and rectal pain [ 95 ].

2.5.4. Radiation

Radiation therapy is regarded as one of the most effective therapies that kills prostate cancer cells using high radiations. Radiations are sent to cancerous cells through various techniques such as brachytherapy (the use of seeds placed in the body) and external beam (where the energy is projected through the skin) to the cancerous sites. Radiation therapy aims at specifically transferring high-energy rays or particle doses directly to the prostate without affecting the normal tissues. These doses are based on the level of prostate cancer. This treatment is considered to be an acceptable therapy for patients who are not suited for surgical procedures [ 96 ]. Various techniques of radiation therapy are discussed below.

Brachytherapy

Brachytherapy includes the direct placement of radioactive sources into the prostate gland with the aid of seeds, injections, or wires under the guidance of transrectal ultrasound. This often involves two techniques: low dose and high dose rates. The low dose rate refers to the permanent implantation of seeds in the prostate tissue, which loses radioactivity gradually [ 97 ], and the latter refers to the supply of a dose of radiation to the prostate tissues with significant risk of leakage to other surrounding organs. The advantage associated with brachytherapy is that it can be completed within a day or less. There is a minimal risk of incontinence in patients without a previous transurethral resection of the prostate (TURP). Erectile function is also not affected. Its disadvantages are usually a requirement for general anesthesia, acute urinary retention risks, and persistent irritative voiding symptoms [ 98 ].

External Beam Radiation Therapy

External beam radiation therapy (EBRT) is a commonly used treatment technique that involves emitting strong X-ray beams specifically targeting the prostate tissues. It radiates higher prostate radiation doses, with less emission to the surrounding tissues. Radiation therapy is considered to be an effective intermediate-risk and high-risk prostate cancer treatment when used together with androgen deprivation therapy (ADT) [ 80 ]. It is a suitable therapy for attenuating metastasizing cancer cells. This technique is more advantageous than surgical therapy. It can treat early stages of cancer, and it is associated with fewer risks such as bleeding, myocardial infarction, pulmonary embolus, urinary incontinence, and erectile dysfunction. It can also relieve symptoms such as bone and joint pain [ 93 ]. Side effects of radiation include urinary urgency and frequency, erectile dysfunction, dysuria, diarrhea, and proctitis [ 97 ].

2.5.5. Radium-223 Therapy

The radium-223 dichloride (Xofigo) technique makes use of a substance used for therapy in patients with metastatic prostate cancer that is resistant to hormone therapy. Its ability to mimic calcium makes radium-223 dichloride be selectively absorbed by the cancer cells in bone tissue. This technique has been reported to have a considerable impact on the survival and recovery of metastatic prostate cancer patients, leading to delayed onset of bone fracture and pain [ 85 ].

2.5.6. Hormonal Therapy

Hormonal therapy is also known as androgen deprivation therapy (ADT). This technique is applied in the treatment of advanced and/or metastasized prostate cancer. Its therapeutic mechanism is based on the blockage of testosterone production and other male hormones, preventing them from fueling prostate cancer cells. Therefore, significantly decreased male hormonal levels are responsible for inhibition of the action of androgen on the androgen receptor [ 99 ]. This is often achieved using bilateral orchiectomy or medical castration via administration of luteinizing hormone-releasing hormone (LHRH) analogs or antagonists. LHRH analog primarily elevates the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by stimulating hypophysis receptors, thus, enabling the drug to downregulate the hypophysis receptors with concomitant reduction of LH and FSH levels, leading to suppressed testosterone production. Leuprolide, goserelin, triptorelin, and histrelin are among the common LHRH agonists. The antagonists cause action by blocking the hypophysis receptors, thereby triggering the immediate inhibition of testosterone synthesis [ 100 ]. ADT has, however, been associated with acute and long-term side effects, such as hyperlipidemia, fatigue, hot flashes, flare effect, osteoporosis, insulin resistance, cardiovascular disease, anemia, and sexual dysfunction [ 101 ].

Flutamide is a type of drugnthat is nonsteroidal and pure antiandrogenic lacking hormonal agonist activity. Flutamide is antiandrogen at the androgen-dependent accessory genitals. Its biological activity is based on 2-hydroxyflutamide. Treating prostate cancer with flutamide and an (LHRH) agonist has produced promising results. In vivo studies of flutamide have shown certain antagonist at the ventral prostate and androgen-dependent seminal vesicles [ 102 , 103 ]. Flutamide is known to result in hepatic dysfunction; however, a study on antiandrogen therapy (AAT) in combination with flutamide indicated that flutamide could be successful when performing regular hepatic function testing during treatment periods [ 104 ]. Maximum androgen blockade (MAB) using flutamide as a second-line hormonal therapy can give a prostate-specific antigen response without side effects, making this a possible treatment option for patients with HRPC with no bone metastases or whose cancer has progressed more than a year following first-line therapy [ 105 ].

Chlormadinone acetate (CMA) is an oral steroidal antiandrogen. Chlormadinone has proven to have anticancer activity. Similar to progesterone used in maximum androgen blockade (MAB) therapy as well as monotherapy for prostate cancer in Japan [ 106 ]. To determine the success of the antiandrogen chlormadinone acetate in treating stage A prostate cancer, a study of 111 patients who received chlormadinone acetate was conducted. The progression rates linked to antiandrogen therapy for stage A1 and A2 patients were lesser in non-treatment receiving groups, concluding that antiandrogen treatment with chlormadinone acetate inhibited the progression [ 107 ]. Chlormadinone is also used to treat benign prostatic hyperplasia, it decreases testosterone level, prostate-specific antigen (PSA) level, and prostate volume, in benign prostatic hyperplasia slowing the progression of Prostate cancer [ 108 ].

2.5.7. Abiraterone

Abiraterone is a second-generation therapy targeted at adrenal and tumor androgen production. It is associated with the irreversible inhibition of the hydroxylase and lyase activities of CYP17A, AR pathways, and 3β-hydroxysteroid dehydrogenase activity, and is used to treat prostate cancer that has metastasized to other parts of the body [ 109 ]. Abiraterone has also been proven to be a potent inhibitor of other microsomal drug-metabolizing enzymes, including CYP1A2 and CYP2D6 [ 109 ]. Clinical data of abiraterone have indicated remarkable results, but there are reports of variable responses and concomitant increasing PSA levels. Abiraterone is correlated with high CYP17A upstream mineralocorticoids, with concomitant side effects including edema, hypertension, fatigue, and hypokalemia [ 110 ].

Immunotherapy or biological therapy is based on stimulating or suppressing the immune system. The treatment uses vaccines designed to work with the patient’s immune system to fight cancer cells. Sipuleucel-T (Provenge) is one of such vaccines, designed for advanced and metastatic prostate cancer cells that have developed resistance to hormone therapy. It is developed from the immune cells by collecting the white blood cells and activating them with prostatic acid phosphatase [ 109 ]. This is then associated with a protein that can trigger the immune system before infusing into the blood [ 99 ]. Sipuleucel-T (Provenge, Dendreon) is an autologous dendritic cell-based immunotherapy used in treating asymptomatic patients by assisting a patient’s immune system in fighting back cancer cells. It is intravenously administered in three doses over one month. Its lesser side effects make it more favorable compared to other chemotherapies. Its side effects include fever, nausea, chills, and muscle aches [ 111 ].

2.5.8. Chemotherapy

Chemotherapy uses anticancer drugs to kill or inhibit the growth of cancerous cells. There has been progress in treatment of prostate cancer after decades of learning and understanding genetics, diagnosis, and treatment. The most common chemotherapy drug for prostate cancer is docetaxel (Taxotere) [ 112 ].

Docetaxel is regarded as the first-line standard therapy for prostate cancer cells that are castration-resistant. It is an antimicrotubule agent which attaches to β-tubulin to inhibit microtubule depolymerization, thereby suppressing mitotic cell division and initiating apoptosis [ 113 ]. CYP3A is a major requirement for the activation of Docetaxel. The development of Docetaxel resistance has been associated with relapse. Docetaxel resistance has been attributed to increased upregulation of the multidrug resistance (MDR) 1 gene that encodes P-glycoprotein [ 114 ].

Cabazitaxel

Cabazitaxel is a novel antineoplastic semi-synthetic derived from the needles of various species of yew trees (Taxus). It is usually sold under the name Jevtana. Cabazitaxel is a second-generation therapy aimed at suppressing docetaxel resistance [ 99 ]. It has a low affinity for Pglycoprotein owing to its additional methyl groups. It is metabolized in the hepatic tissues by CYP3A4/5 and CYP2C8 (10–20%). Hypotension, bronchospasm, renal failure, neurotoxicity fatigue, alopecia, and generalized rash/erythema are among the common side effects associated with its use. There have also been reports of diarrheal deaths related to Cabazitaxel therapy resulting in electrolyte imbalances and dehydration [ 114 ].

Enzalutamide

Enzalutamide is a second-generation AR inhibitor that was recognized as one of the chemotherapeutic drugs for prostate cancer in 2012. This drug focuses on the androgen pathway and has functions such as (1) competitively inhibiting the binding of androgen to the androgen receptor, (2) inhibiting nuclear translocation and recruitment of cofactors, and (3) inhibiting the association of the activated androgen receptor. Enzalutamide targets androgens such as testosterone and dihydrotestosterone. Its therapeutic mechanism includes:

• Competitive inhibition of androgen binding to the androgen receptor;
• Inhibition of nuclear translocation and co-factor recruitment;
• Inhibition of the binding of DNA with activated androgen receptor.

The side effects of enzalutamide include fatigue, asthenia, diarrhea, and vomiting [ 115 ].

2.6. Combination Therapy

Combination therapy has been demonstrated as an effective strategy for prostate cancer treatment. Combination therapy is a strategy that was developed to treat castration-resistant prostate cancer and other forms of prostate cancer. There are no drugs to date that treat castration-resistant prostate cancer (CRPC), and currently approved treatment options either used alone or in combination therapy are useful in extending a patient’s lifespan by a few months [ 116 ]. Current treatment options used for the treatment of prostate cancer are not curative, and disease progresses to the castration-resistant phenotype over a period of time. Combination therapy with currently used treatment options for prostate cancer could successfully increase a patient’s lifespan and suppress tumors. Amongst all the available treatment strategies available for metastatic prostate cancer, androgen deprivation therapy (ADT) has more potential combination treatment compared to other therapeutic strategies for prostate cancer, and approved and currently ongoing clinical trials with ADT treatment include ADT with radiation therapy, which often treats high-risk patients to delay or prevent the disease from progressing to CRPC; (ii) ADT and chemotherapy, which in several clinical studies has shown to increase patient survival but results in adverse side effects and sometimes death; and (iii) immunotherapy and ADT, which has been reported to increase patient survival by 8.5 months [ 117 ]. Clinical trials are ongoing to analyze the effects of survival in ADT and the PSA-targeted poxviral vaccine, PROSTVAC-IF; a combination of radiation therapy with immunotherapy under ADT; a combination of chemotherapy with immunotherapy under ADT; and a combination of docetaxel under ADT [ 118 ]. There are a number of completed and ongoing clinical studies/trials for combination therapy of prostate cancer. Some of the clinical trials are listed in Table 5 and Table 6 .

Combination therapies for prostate cancer—completed clinical trials [ 116 ].

Combination therapies for prostate cancer—ongoing clinical trials [ 116 ].

2.7. Drug Repurposing

Drug repurposing, also known as drug repositioning, reprofiling, or retasking, is a way of identifying new uses for approved drugs [ 119 ]. The advantage of drug repurposing over de novo drug development (developing new drugs) is that repurposed drug candidates have undergone extensive research in animal models and clinical trials, testing the safety, optimization, and, in most cases, formulation development of the drug, as well as pharmacokinetic and pharmacodynamic properties. This advantage usually speeds up the research and development for new use of the drug and reduces the failure rate in later efficacy testing clinical trials [ 120 ]. These previously tested drugs can rapidly progress into phase II and phase III human clinical studies, which implies that the associated drug development cost could be drastically deceased. Researchers show great interest in this phenomenon because drug repurposing alleviates the dilemma of some challenges currently faced in clinical research for finding new cancer therapies, such as drug shortage. It can take a period of 10–17 years for a development of a new drug compared to 3–12 years for repurposed drugs. Technology advances play a major role in scanning large databases and detecting key molecular similarities in different diseases to identify drugs that can be repurposed. Androgen deprivation therapy (ADT) is used to treat advanced-stage prostate cancer patients. Metformin is a drug commonly used to treat type II diabetes, repurposed to treat prostate cancer. It can be utilized to sensitize prostate cancer to the currently used standard prostate cancer therapies and improve the efficacy of treatment. It is reported that Metformin is able to increase the effectiveness of ADT for the treatment of prostate cancer [ 121 ]. Here, we discuss three main categories of drug repurposing studies for PCa, classified by different discovery and validation categories, such as the knowledge and ability of the drug to be researched. For example, ormeloxifene, a selective estrogen receptor modulator, is known for its anticancer properties in several cancers such as breast and ovarian cancers, but ormeloxifene is reported to have mediated the inhibition of oncogenic β-catenin signaling and EMT progression in prostate cancer by significantly suppressing β-catenin/TCF-4 transcriptional activity, N-cadherin, MMPs, and triggering pGSK3β expression. The other category is drugs that have been tested in assays and classified in accordance with their activity. For example, Itraconazole, an antifungal drug responsible for preventing angiogenesis and the initiation of the Hedgehog signaling pathway, was experimented in phase II clinical trials and established to be effective in patients with metastatic CRPC [ 122 ]. Table 7 shows different drugs repositioning candidates in prostate cancer clinical trial studies.

Anticancer drug repositioning candidates under clinical investigation for the treatment of prostate cancer [ 32 ].

Other anticancer drugs that are currently being researched in vitro and in vivo for treatment of prostate cancer include naftopidil, an alpha blocker; niclosamide, an anti-helminthic agent; ormeloxifene, an estrogen receptor modulator; nelfinavir, an antiretroviral agent; glipizide, an antidiabetic agent; clofoctol, an antibacterial agent; and triclosan, an antibacterial agent [ 32 ]. Drug repurposing for prostate cancer presents an opportunity to address current treatment challenges. This strategy should be implemented using computational genomic and proteomic tools to assist and guide researchers in their decision making regarding patient treatment [ 122 ].

2.8. Treatment Challenges

Despite the various treatment options, mCRPC remains to be an incurable disease. Over time, the disease continues to develop resistance to different conventional treatment options [ 123 ]. This has led to continuous research on understanding the growth, metastasis, tumorigenesis, tumor microenvironment, and tumor environmental interactions that promote disease progression.

2.8.1. Drug Resistance

Castration resistance has been reported in prostate cancer that has reached advanced stages. Castration resistance allows for androgen signaling via amplification of the androgen receptor’s synthesis of the intra-tumoral hormone, while disrupting the androgen receptor’s coexpressors and coactivators [ 124 ]. Resistance to enzalutamide and abiraterone acetate, as well as gene mutation in metastatic prostate cancer, has been attributed to the overexpression of the active androgen receptor (AR) in patients. Prostate cancer often develops owing to androgens; thus, most treatments are targeted at blocking androgen hormones. This is beneficial to anticancer drug-resistant patients.

Mutations have also been shown to contribute to drug resistance in cancer cells, allowing for bypassing of the targeted pathways. Alterations in intrinsic pathways such as the AR signaling pathways, MAPK/ERK pathway, endothelin A receptor (EAR), and Akt/PI3K pathways as well as exacerbated expression of the androgen receptor have been shown to contribute to ADT resistance [ 46 ].

2.8.2. ABC Transporters

These transporters are expressed in the plasma membrane, where they serve as efflux pumps and are well-known triggers of multidrug resistance. They transport drugs and xenobiotics in and out of the cells [ 125 ]. Multidrug resistance protein (MRP) transporters MRP2, MRP3, MRP4, and MDR-1 protein (P-glycoprotein) have been reported in prostate cancer [ 110 ]. The exacerbated expression of these transporters has been implicated in the increased efflux of drugs, thereby leading to multidrug resistance. Of these transporters, MRP2 has been reported to exhibit the highest potency of resistance to natural product agents, MRP3 exhibits the lowest resistance to etoposide, and MRP4 and MRP5 are responsible for resistance to nucleoside analogs and transport cyclic nucleotides. MRP4 also influences resistance to chemotherapeutic agents such as camptothecins, cyclophosphamide, topotecan, methotrexate, and nucleoside analogs [ 126 ].

2.8.3. Cytochrome P450

Cytochromes P450 are a well-known multigene superfamily of heme-containing monooxygenases that are both constitutive and inducible. They catalyze the metabolism of a variety of xenobiotics and endocrine disruptors [ 127 ]. The family including CYP2C19, CYP4B1, CYP3A5, CYP2D6, CYP1A2, and CYP1B1, has been reported in human prostate cells [ 128 ]. CYP4B1′s main functions are the metabolism and activation of arylamines via N-hydroxylation, an activity that results in bladder tumor [ 129 ]. Exacerbated expression of CYP1B1 has been implicated in the advances of drug resistance in prostate cancers. This is often achieved by 2-hydroxylation of flutamide [ 130 ]. CYP17A speeds up the process of sequential hydroxylase and the lyase steps in the androgen biosynthetic pathway in humans, thus, making it a critical therapeutic marker for prostate cancer treatment [ 131 ].

2.8.4. Mutations in Androgen Receptors

Mutations in androgen receptors occur owing to a disorder in androgen sensitivity. Androgen receptor (AR) signaling plays an important role in the development, activity, and homeostasis of the prostate gland. It regulates the process of gene transcription via attaching to the androgen response elements on specific genes, as well as allowing nuclear translocation of the androgen receptor [ 132 ]. Gene changes in the AR signaling pathway ( Figure 2 ) have been reported in prostate cancers. AR mutations were first reported in an androgen-responsive cell line, LNCap. These mutations have been implicated in the development of AR resistance arising from AR-targeted therapy [ 133 ]. This has led to the use of androgen deprivation therapy (ADT) and antihormone therapy in the treatment of advanced prostate cancer. The majority of AR mutations result in single amino acid substitutions, which are mostly found in the AR androgen-binding domain. The mutation T877A, which has been found in roughly 30% of metastatic CRPC patients, is the most common [ 134 ]. Other mutations have resulted in enhanced AR binding to coregulators, resulting in higher AR transcriptional activity vis-à-vis H874Y and W435L mutations. These mutations have been implicated in the development of AR resistance arising from AR-targeted therapy [ 124 ]. Figure 3 illustrates the transcription activity of the androgen receptor gene [ 135 ].

The function of AR signaling in prostate cancer and development: ( A ) Prostate homeostasis is maintained in a healthy prostate via reciprocal signaling between the stromal and epithelial layers; ( B ) normal prostate cells are converted into cancer initiating cells by unknown mechanisms, histological evidence of prostatic intraepithelial neoplasia and early cancer lesions appears, cells at the basal layer express higher levels of AR in response to this event; ( C ) cellular and molecular alterations occur in prostate adenocarcinoma, resulting in luminal cells with the AR transcriptional pathway; ( D ) Prostate cancer cells in CRPC maintain AR activity through other mechanisms (including upregulation of AR and its splice variants, intra-tumoral androgen synthesis, cross communicate with other signal pathways, and increased/altered expression of AR cofactors) as the availability of androgen from the blood steam becomes limited [ 134 ].

The androgen receptor gene encodes a 110 kD protein composed of 919 amino acids that are classified by an androgen-binding domain (ABD), a conserved DNA-binding domain (DBD), and an N-terminal transactivation domain, which has two polymorphic trinucleotide repeat segments. These repeated segments, consisting of variable numbers of polyglycine repeats and polyglutamine, highly influence the androgen receptor transcription activity. The gene transcript consists of eight exons in total: exon 1 codes for the N-terminal domain, exons 2–3 code for the DBD, and exons 4–8 code for the ABD [ 135 ].

2.8.5. Tumor Microenvironment

The tumor microenvironment has a crucial role in the development and progression of prostate cancer to the advanced stage, as per recent studies. According to experimental research, the milieu and malignant tumor cells have a mutually reinforcing relationship in which early changes in the microenvironment of normal tissue can foster carcinogenesis and tumor cells can foster more protumor modifications in the microenvironment [ 136 ]. A tumor microenvironment comprises a wide interlinked niche encompassing the extracellular matrix and specialized cells such as neural cells, blood vessels, immune cells, and mesenchymal/stromal stem cells, all of which secrete factors such as chemokines, cytokines, and matrix-degrading enzymes. They interact with cancer cells through paracrine and autocrine mechanisms [ 137 , 138 ].

According to a tumor stage-specific histological investigation, high-grade PC is linked to enhanced stromal immune cell infiltrates with a variety of cellular types [ 139 ]. Chronic stresses such as direct infection, urine reflux, a high-fat diet, and estrogens affect the prostate’s ability to become inflamed on a long-term basis [ 140 ]. The stromal compartment experiences an inflow of several immune cells, including CD3+ T-cells, macrophages, and mast cells, amid ongoing inflammation [ 141 ]. High levels of cytokines and chemokines, primary tumor necrosis factor, nuclear factor kappa B, to mention a few, are produced by inflammatory cells. The regulation of angiogenesis, cellular proliferation, and inflammation involves these proteins among others. They control the PC’s shift to the malignant phenotype [ 136 ].

The surrounding stromal agents go through complex modifications as a result of the interaction between prostatic epithelial cells and the tumor microenvironment, and these changes control the severity of the disease, its capacity to spread, and its susceptibility to traditional treatments [ 142 , 143 ].

2.9. Role of Estrogen Receptors (ERs) in Prostate Cancer Etiology and Progression

Prostate cancer is often regarded as hormone dependent, since steroid hormones direct its initiation and progression. Earlier reports have emphasized the significance of steroid levels in the etiology of PCa [ 144 , 145 ]. Estrogen plays an indispensable role in the secretion of male sex hormones, and it also plays cardinal roles in the growth, differentiation, and homeostasis of prostate tissues. Estrogens also contribute to the development of prostate cancer [ 146 ]. In a report from Ellem and Risbridger using aromatase knockout (KO) mice, the knockout mice could not metabolize androgens to estrogens, and it was observed that high levels of testosterone led to the development of prostate gland enlargement (prostatic hyperplasia). Meanwhile, increased estrogen and decreased testosterone levels gave rise to inflammatory events and lesions [ 147 ]. Epidemiological studies have also proposed that the serum level of estradiol and the serum estradiol/testosterone (E/T) ratio influence the initiation of PC and its progression [ 148 ]. Estrogen activities are carried out by two receptors, which are estrogen receptor α (ERα) or β (ERβ); ERα and Erβ are expressed in prostate tissue [ 125 ]. ERα is confined to the prostatic stroma, and has an indirect effect on the epithelial cells, while ERβ is found to be expressed within the epithelial domain and regulates epithelial proliferation and differentiation [ 149 ]. No less than five ERβ homologues (ERβ1, -2, -3, -4, and -5) exist in humans [ 145 ]. ERβ1 plays a functional role, while the other isoforms control its activity. The role of ERβ may consequently depend on the ratio of expression of ERβ1 and ERβ isoforms. It is known that ERα brings about the adverse effects induced by estrogens, while ERβ directs the protective and anti-apoptotic effects of estrogen in PCa [ 149 ]. On the one hand, the expression of estradiol receptor α has been found to be remarkably linked with a high Gleason’s score and poor survival rate in patients with PCa [ 150 ]; on the other hand, ERβ expression was found to be decreased or lost in the examined PCa samples [ 151 ]. Furthermore, the expression of ERβ2 and ERβ5 together has been shown to constitute a marker for biochemical relapse, post-surgery spread/metastasis, and the period to spread after radical prostatectomy in PCa patients. Based on the aforementioned, the expression of ERβ1 decreased, and that of ERβ2 and ERβ5 increased with the progression of PCa. This expression pattern corresponded with the spreading and metastasis of PCa [ 152 ]. In PCa, on the one hand, ERα has an oncogenic role and directs the deleterious effects of estrogen, which include proliferation, inflammation, and prostate carcinogenesis. Erβ, on the other hand, may elicit antitumor activity (oncosuppressor) in PCa manipulation of ERβ by ligands. Novel drug candidates might be useful in the therapeutic strategies towards PCa, specifically during the earlier stages of the disease [ 145 ].

2.10. Experimental Work Exploring Alternative Treatments

Traditional medicine in prostate cancer medicine in prostate cancer treatment.

Traditional medicine plays a significant role in healthcare in developing countries, and such countries also have a long history of treating different diseases and ailments. The use of medicinal plants in cancer has gained substantial attention, and recently, research is ongoing, with the National Cancer Institute (NCI) playing a pivotal role in the research of traditional medicine to treat cancer [ 153 ]. Traditional medicine is used significantly by patients with cancer to minimize side effects or used entirely as a single treatment rather than conventional therapy. This is because plants are easily accessible, effective, and affordable. Plant-derived compounds and plant extracts have been widely used due to their anti-inflammatory, antioxidant, and antimicrobial properties [ 154 ]. Various anticancer agents used in therapy today are derived from plants, for example, paclitaxel and taxol are derived from Taxus brevifolia , docetaxel (Taxotere) from Taxus baccata , and vincristine and vinblastine from Catharanthus roseus [ 155 ].

There is considerable proof supporting the utilization of a plant-based diet for the prohibition of acute disorders. Consumption of plant-based food provides necessary nutritional supplements and phytochemicals that aid in growth and shield against the occurrence of various acute illnesses [ 156 ]. They also offer protection against oxidative stress related to chronic disorders such as cancer. Phenolic compounds serve protective roles including antibacterial, anti-inflammatory, and anticancer roles [ 157 ]. Plants containing organosulfur compounds have chemoprotective activity. Carotenoids and polyphenols have anti-inflammatory and antioxidant activity [ 158 ]. Consequently, medicinal plants are commonly used for the treatment of cancers [ 159 ]. Several flavonoids have shown anticancer activity in the treatment of prostate cancer. Flavonoids are polyphenolic compounds characterized by a benzene ring condensed with a six-member phenyl ring attached to the carbon 2 and carbon 3 (C2 and C3) carbon positions. Among flavonoids, flavonols which can be identified by a distinctive hydroxyl group at the carbon 3 carbon position, have been reported in a number of studies, both preclinical and clinical, for their anticancer activity in prostate cancer cell lines. Flavonols, myricetin, fisetin, and kaempferol are commonly found in several fruits and vegetables and display anti-inflammatory, antiviral, antineoplastic, antibacterial, and antioxidant activity, among many others, in different cells [ 160 ].

Several specific plants have been analyzed for their activity as anticancer agents for cancer treatment. Plant anticancer activity is linked to phytochemical constituents present in extracts. Table 8 summarizes various medicinal plants used in cancer treatment [ 161 ].

Summary of various medicinal plants used against different types of cancers [ 161 ].

2.11. Gene Therapy

The developments achieved in genetics, biotechnology, tumor biology, and immunology have facilitated new advancements in gene therapy. Gene therapy is a therapy that includes inserting or deleting a DNA sequence or base pair to rectify a genetic defect in a specific protein or to target a certain molecular pathway. A few gene editing technologies are currently being developed for gene therapy. Gene therapies usually involve the encapsulation of DNA nucleotides into viral and non-viral vectors that deliver the gene to a specific site, then, inserting the gene into the human genome to edit the DNA sequence and regulate cellular processes [ 162 ]. The main idea of gene therapy is to deliver exogenous nucleotides to specific DNA parts in the cells of various tissues. Viruses are well known for being efficient in transferring their genome into a host to infect it. The viral vector can be administered intravenously by injecting it directly into the targeted tissue. Non-viral vectors such as nanoparticles and polymers have also been studied for their use in gene therapy for the treatment of prostate cancer. These non-viral vectors usually condense DNA through electrostatic interactions, which also protects the genetic material from degrading. Gene therapies also explore the use of apoptosis. Failure of cells to undergo apoptosis can lead to uncontrolled cell division, which then leads to the development of cancer [ 163 ]. The suppression of apoptosis usually occurs as a result of the genetic mutations in cancerous cells. Gene therapy for prostate cancer targets apoptosis cellular pathways by introducing a gene that encodes a mediator or inducer of apoptosis in defective cells encoding an inducer, mediator, or executioner of apoptosis. Apoptosis-inducing genes, such as caspases, induce cell death in cancer cells [ 164 ]. Numerous challenges such as enhancing DNA transfer efficiency to cells, as well as immune responses that interfere with gene expression lie ahead for gene therapy. However, irrespective of the difficulties, it is definite that gene therapy will be the next up-and-coming medical technique used against prostate cancer in the future. Some clinical trial studies investigating prostate cancer therapy using gene therapy include various transgenes such as p53 and herpes simplex tk [ 165 ]. Recently used prostate cancer gene therapy procedures involve rectifying abnormal gene expression, utilizing programmed cell death mechanisms and biological pathways, specifically targeting important cell functions, initiating mutant or cell lytic suicide genes, strengthening the immune system anticancer response, and connecting treatment with radiation therapy or chemotherapy [ 166 ]. Animal studies in prostate cancer gene therapy have made use of intraprostatic administration of gene therapy delivery systems. This route of administration has been found to be more effective, as most of the dose was delivered directly to the prostate. This targeted delivery allowed the administered dose to reach prostate cancer metastasis. Lactoferrin and transferrin are multifunctional proteins that can bind to iron-binding proteins that are usually overexpressed on prostate cancer cells [ 167 ]. The proteins are responsible for regulating free iron levels. High iron levels have negative side effects such as increasing the risk of bacterial infections, as well generating free radicals and promoting the conversion of oxidation states ferrous ion (Fe2+) to ferric ion (Fe3+). Various studies in animals have used transferrin and lactoferrin for active targeting of prostate cancer cells. Prostate stem cell antigen (PSCA) is a cell surface antigen that is expressed in androgen-dependent and androgen-independent prostate cancer cells; therefore, it can be used as a marker for prostate cancer. Human epidermal growth factor receptor 2 (HER2) is another ligand that can be used as a marker for targeted treatment of prostate cancer due to mutations causing overexpression of tumor cells [ 168 ]. A study conducted on prostate cancer-induced xenograft mice models indicated that the inhibition of HER2 and epidermal growth factor receptor (EGFR) by specifically targeting tumor-initiating cells could highly improve the efficacy of the chemotherapy treatment for castration-resistant prostate cancer with activated STAT3, and could prevent metastasis EGF-induced STAT3 phosphorylation, which is responsible for enabling prostate cancer metastasis [ 169 , 170 ]. Various gene targeting systems have experimented on immune response treatment with a DAB-Lf dendriplex encoding IL12, which has demonstrated drastic tumor reduction in the PC3 and DU145 prostate tumors. MiRNA (miR)-205, miR-455-3p, miR-23b, miR-221, miR-222, miR-30c, miR-224, and miR-505 are downregulated in patients with prostate cancer and are known to be associated with tumor suppressors in prostate cancer cells, affecting proliferation, invasion, and aerobic glycolysis. MiR-663a and miR-1225-5p are linked to the development of prostate cancer, showing potential to be used as candidate markers. The specific functions of miR-663a and miR-1225-5p in stimulating prostate cancer growth and tumor progression are unclear [ 171 , 172 , 173 ].

2.12. CRISPR Cas9

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) is a natural defense mechanism found in archaea and bacteria. This system is currently being extensively researched because of its simplicity and effectiveness [ 145 ]. The ability to target intraprostatic inoculation of specific gene therapy vectors is an advantage of immunotherapy-based and cytotoxic gene therapy approaches. Because changes in DNA sequences result in mutations that cause cancer, scientists have been interested in new approaches to correct such changes by manipulating DNA [ 174 ]. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system uses single-guide RNA (sgRNA) to identify and bind to certain DNA sequences through Watson–Crick base pairing [ 175 ]. CRISPR and the CRISPR–Cas9 (CRISPR-associated 9) system have been extensively studied and have changed the study of biological systems. CRISPR allows the precise altering, inserting, or deleting of DNA nucleotides in the target DNA sequence by initiating double-strand breaks. A guide RNA binds to Cas9, leading it to a complementary DNA target sequence, where a double-strand break is inserted to repair or edit DNA nucleotides. CRISPR can also be used for detecting DNA from RNA from cancerous cells and cancer-causing viruses. CRISPR/Cas9 delivery in nanoparticle lipid-based vectors is safer to use and effective [ 176 ]. Liposomal vectors offer a wide range of advantages and modifications, giving direct control over the physico-chemical properties of the liposomal surface, and can accommodate the conjugation of targeting ligands. An antibody-targeted delivery system of lipid nanoparticles (LNPs) was initially developed and standardized for the targeted treatment with small interfering RNA (siRNA). Recently, LNPs were used in a proof-of-concept study to target disseminated ovarian cancer in mice with CRISPR/Cas9 [ 177 ]. A study by Ye et al., 2017, analyzed the function of GPRC6A in the progression of prostate cancer progression in vitro and in animal studies. The study indicated that GPRG6A was expressed in human prostate cancer cell lines, and also showed polymorphism that improved mTOR signaling. Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 nuclease (Cas9) (CRISPR/Cas9) were used to interrupt the GPRC6A gene in the PC-3 cell line. The results indicated that editing the GPRC6A gene using CRISPR/Cas9 stopped cell proliferation and migration in vitro, and also that osteocalcin activated the ERK, AKT, and mTOR signaling pathways. It was found that the GPRC6A gene mediated the progression of prostate cancer in animal studies mainly through assessing the response to osteocalcin in human prostate cancer xenograft models with cells expressing GPRC6A gene or the CRISPR/Cas9-mediated deletion of the gene. The findings of the study supported the use of CRISPR as a potential therapeutic target [ 178 ]. The first genome-scale CRISPRi screen in metastatic PCa models indicated that kinesin family member 4A (KIF4A) and WD repeat domain 62 (WDR62) initiate aggressive PCa. Novel targets for prostate cancer are also provided by CRISPR screen in prostate-specific cell lines, also suggesting the importance of assessing the results in other cancer cells, which may lead to the discovery of biomarkers for prostate cancer therapy [ 179 ].

2.13. Nanotechnology

Nanotechnology is an integrative field that combines pharmacology, biomedical science, and nanotechnology. Nanoparticles have characteristics that allow drug efficacy, can easily penetrate tumors, prevent drug degradation, and can be modified to target specific tissues [ 170 ]. Nanoparticles such as liposomes, polymers, metal nanomaterials, and porous silicon nanoparticles have been highly researched for application in prostate cancer treatment and prognosis. Active targeting nanoparticles have modified surfaces with attached antibodies, affibodies, peptides, or oligosaccharides. These targeting ligands target receptor cells on cancerous cells, such as the prostate-specific membrane antigen (PSMA) receptors on prostate cancer cells [ 180 ]. There is interest in developing nanoparticles for prostate cancer therapy due to challenges faced by currently used treatments. A study conducted at Mount Sinai New York on 16 patients used gold silica nanoparticles for localized prostate cancer. The gold silica nanoparticles absorbed infrared light at a wavelength that could penetrate biological tissues. The gold nanoparticles possessed plasmon resonance that could drastically decrease side effects related to the therapy. Patients were injected intravenously with gold nanoparticles with laser ablation. The growth of the tumor was analyzed using magnetic resonance imaging after 48 and 72 h of therapy. The results showed a decrease in tumor size with no side effects. While only a few studies have progressed to clinical trials, a study on targeted and controlled release for prostate cancer therapy has recently started clinical trials, which has led to the development of the BIND-014 docetaxel encapsulated nanoprototype [ 155 ]. The results of preclinical and clinical improvements linked to liposomal drug delivery in cancer treatment suggest that liposomal encapsulation signals a positive future for the treatment of prostate cancer. Nanocarriers have been demonstrated as useful in combination therapy, as they are able to overcome differences in pharmacokinetics in chemotherapeutic agents [ 173 ]. Combining nanotechnology and other therapeutic strategies can effectively enhance and improve the effectiveness of drugs. In prostate cancer, nanotechnology is used in diagnostics and therapeutic treatment. Not only are nanoparticles effective delivery systems, but they also improve the solubility of poorly soluble drugs, and multifunctional nanoparticles display adequate specificity toward urological cancers, bladder, renal, and prostate cancer. In a study conducted by Zhang et al., the encapsulation of docetaxel and doxorubicin in nanoparticles increased the observed cytotoxicity in prostate cancer cells [ 180 ]. Another study, conducted to assess the codelivery of doxorubicin (DOX) and docetaxel (DOC) by nanocarriers for synergistic activity, suggested that both anticancer agents DOX and DOC in the nanoparticles acted synergistically and promoted the curative effect of Dox and Doc in a xenograft mouse model, which acted on androgen-dependent and androgen-independent prostate cancer cell lines [ 181 ]. A multicenter phase II open-label clinical trial consisting of 42 patients with progressing mCRPC who received abiraterone acetate and/or enzalutamide treatment studied the safety and efficacy of a docetaxel-containing nanoparticle (BIND-014) targeting prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. Targeted delivery of docetaxel by prostate-specific membrane antigen (PSMA)-conjugated nanoparticles was found to be clinically effective, drastically reducing circulating tumor cells [ 182 ]. A modern method of heating tumors after inoculation of magnetic nanoparticles has been extensively researched in prostate cancer clinical trials. The feasibility and tolerability were evaluated with the first prototype of an alternating magnetic field applicator in a study experimenting with magnetic nanoparticle thermotherapy alone or in combination with permanent seed brachytherapy. The results reported that magnetic nanoparticle thermotherapy had been shown to be hyperthermic and effective to thermoablative temperatures and could be achieved in the prostate at low magnetic field strengths of 4–5 kA/m [ 183 , 184 ].

2.14. Next-Generation Sequencing

Recently, the development of next-generation sequencing (NGS) technologies has proven to be a substantial advancement in the documentation of unique genetic alterations that have improved our understanding of cancer cell biology [ 185 ]. Precision medicine, also known as personalized medicine, strives to produce individualized treatment plans and do away with “one-size-fits-all” approaches to therapy [ 186 ]. The development of personalized treatment was supported by NGS, which not only increased our understanding of cancer but also gave oncologists a strong tool for understanding each patient’s disease and its distinct genetic characteristics and whole-genome mutational status [ 187 , 188 ]. NGS can identify tumor-specific alterations with single-nucleotide resolution [ 189 ]. The NGS technologies are whole-genome, whole-exome, RNA, reduced representation bisulfite, and chromatin immunoprecipitation sequencing. The three crucial phases in NGS are library preparation and amplification, sequencing, and data analysis [ 190 ]. Even though the Sanger sequencing and PCR methods have long been used to examine tumor biomarkers, the development of NGS has made it possible to screen more genes in a single test. Predictive biomarkers have subsequently been developed to assist in selecting the right patient populations for clinical investigations. Additionally, NGS enables researchers to identify the most prevalent known variants as well as the long tail of uncommon mutations that occur in less than 1% of patients and can offer helpful data on treatment sensitivity [ 187 ].

The application of NGS in PC genomics has significantly advanced the systematic cataloging of all DNA alterations occurring in cancer [ 188 ]. The identification and production of novel long non-coding RNAs and novel gene fusions in PC have been greatly aided by the use of RNA sequencing. This has resulted in the discovery of new recurrent alterations that have been identified, which are TMPRSS2-ERG translocation, SPOP and CHD1 mutations, and chromoplexy, and also the pathways that have been previously well-established have been validated (e.g., androgen receptor overexpression and mutations; PTEN, RB1, and TP53 loss/mutations) [ 189 , 190 ]. DNA sequencing is now far more sensitive and scaleable due to NGS [ 191 ]. PC continues to present a significant challenge in terms of diagnosis and prognosis due to its highly diverse nature [ 192 ]. To more accurately determine the cancer’s aggressiveness, clinicopathological and radiological data should be combined with the knowledge gathered from NGS investigations [ 193 , 194 ]. Despite having great hopes for NGS benefits, there are a number of limitations to the method that should be taken into consideration [ 194 ]. Firstly, there are valid arguments against NGS replacing established and thoroughly supported histopathological diagnoses. Although NGS can often be utilized to identify and subtype various cancer entities, an accurate pathological examination should always come first [ 195 ]. Second, NGS from tumor biopsies only provides limited temporal and geographical resolution of the entire tumor since it can only evaluate DNA and RNA changes in a small group of tumor cells at a particular timepoint [ 196 ]. This issue can be approached from a variety of angles, including improving spatial resolution through novel techniques, single-cell sequencing, serial analysis of circulating cell-free nucleic acids or tumor cells, or pragmatically focusing on the actionability of specific targets via functional studies [ 197 ]. Third, the creation of the software tools required for the analysis and clinical interpretation of the “big data” produced by NGS to support clinical decision making is still lagging behind the hardware infrastructure that is currently in place for its calculation, management, and storage [ 198 ]. Additionally, significant bioinformatical work is required to directly compare data obtained on various NGS platforms and evaluated by various bioinformatic pipelines and algorithms. Therefore, the success of NGS and precision oncology depends greatly on efficient communication and constructive teamwork among all parties [ 199 ].

3. Conclusions

Prostate cancer is one of the leading causes of death in men globally, after lung disease. Commonly mutated genes, proteins, and pathways associated with an increased risk of prostate cancer development can be used as biomarkers for the disease, which provide information on the stage and cause of cancer. Biomarkers can also give specifications on the type of treatment required for cancer. There is an urgent need for effective and targeted specific treatment for prostate cancer. The current treatments available for prostate cancer are beneficial to only a few patients, and present numerous side effects that eventually affect the quality of life of most patients. Chemotherapy, radiotherapy, and hormonal treatment have adverse side effects, including drug resistance, which remains a setback to anticancer treatment. Many medicinal plants, gene therapy, and the application of nanotechnology currently in research have proven to reduce side effects as well as restore chemosensitivity in resistant tumor cells. Medicinal plant fractions and compounds, genetic material encapsulated in target-specific nanocarriers with controlled release, and targeted therapies based on cellular pathways appear to be promising alternatives for prostate cancer treatment.

Funding Statement

Reference: TTK200415513610, NRF grant no 129891.

Author Contributions

M.S., supervision—oversight and leadership of the research, planning and execution, critical review and editing of the manuscript, funding acquisition; K.R., summary, introduction, abstract, genetics, diagnosis, treatment options, alternative approaches, conclusion and referencing, review and editing, project administration; P.M., summary, introduction, abstract, genetics, diagnosis, treatment options, alternative approaches, conclusion and referencing; L.G., summary, introduction, abstract, diagnosis, treatment options, alternative approaches, conclusion referencing; A.A., genetics, treatment options, critical review and editing of the manuscript; S.M., review and editing of the manuscript. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of this review.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Together we are beating cancer

• Cancer types
• Breast cancer
• Bowel cancer
• Lung cancer
• Prostate cancer
• Cancers in general
• Clinical trials
• Causes of cancer
• Coping with cancer
• Managing symptoms and side effects
• Mental health and cancer
• Money and travel
• Death and dying
• Cancer Chat forum
• Health Professionals
• Cancer Statistics
• Cancer Screening
• Learning and Support
• NICE suspected cancer referral guidelines
• Make a donation
• By cancer type
• Leave a legacy gift
• Donate in Memory
• Find an event
• Race for Life
• Charity runs
• Charity walks
• Search events
• Relay for Life
• Volunteer in our shops
• Help at an event
• Help us raise money
• Campaign for us
• Do your own fundraising
• Fundraising ideas
• Get a fundraising pack
• Return fundraising money
• Fundraise by cancer type
• Set up a Cancer Research UK Giving Page
• Find a shop or superstore
• Become a partner
• Cancer Research UK for Children & Young People
• Our Play Your Part campaign
• Brain tumours
• Skin cancer
• All cancer types
• By cancer topic
• New treatments
• Cancer biology
• Cancer drugs
• All cancer subjects
• All locations
• By Researcher
• Professor Duncan Baird
• Professor Fran Balkwill
• Professor Andrew Biankin
• See all researchers
• Our achievements timeline
• Our research strategy
• Involving animals in research
• Research opportunities
• For discovery researchers
• For clinical researchers
• For population researchers
• In drug discovery & development
• In early detection & diagnosis
• For students & postdocs
• Our funding schemes
• Career Development Fellowship
• Discovery Programme Awards
• Clinical Trial Award
• Biology to Prevention Award
• View all schemes and deadlines
• Applying for funding
• Start your application online
• How to make a successful applicant
• Funding committees
• Successful applicant case studies
• How we deliver research
• Our research infrastructure
• Events and conferences
• Our research partnerships
• Facts & figures about our funding
• Develop your research career
• Recently funded awards
• Manage your research grant
• Notify us of new publications
• Find a shop
• Volunteer in a shop
• Donate goods to a shop
• Our superstores
• Shop online
• Wedding favours
• Cancer Care
• Flower Shop
• Our eBay store
• Shoes and boots
• Bags and purses
• We beat cancer
• We fundraise
• We develop policy
• Our global role
• Our organisation
• Our strategy
• Our Trustees
• CEO and Executive Board
• How we spend your money
• Early careers
• Your development

Cancer News

• For Researchers
• For Supporters
• Press office
• Publications
• Update your contact preferences
• About cancer
• Get involved
• Our research
• Funding for researchers

The latest news, analysis and opinion from Cancer Research UK

• Science & Technology
• Health & Medicine
• Personal Stories
• Charity News
• Science & Technology

Artificial intelligence reveals prostate cancer is not just one disease

29 February 2024

Research published in Cell Genomics today  has shown that prostate cancer, which affects one in six men in the UK in their lifetime, includes two different subtypes of the disease, also known as evotypes.   

This discovery was made by using artificial intelligence (AI) to help unlock new discoveries about the evolution of prostate cancer.   

Just as humans – or Homo sapiens – have evolved into a species over time from our ancestors, the development of cancer is also an evolutionary process. By looking at the evolutionary tree of cancer, we can find out a lot about the disease, and it can even help us develop new treatments.  

“Our research demonstrates that prostate tumours evolve along multiple pathways, leading to two distinct disease types,” said lead researcher Dr Dan Woodcock, of the Nuffield Department of Surgical Sciences at the University of Oxford.    

“This understanding is pivotal as it allows us to classify tumours based on how the cancer evolves rather than solely on individual gene mutations or expression patterns.”  

The power of AI  

The study, funded by Cancer Research UK and Prostate Cancer Research, involved researchers working together as part of an international consortium, called The Pan Prostate Cancer Group, from the University of Oxford, the University of Manchester, the University of East Anglia and the Institute of Cancer Research, London.   

The researchers analysed the DNA of prostate cancer samples in 159 patients using whole genome sequencing – a comprehensive way of looking at the entirety of someone’s genetic material.   

They then used an AI technique known as neural networks to compare the DNA of the different samples.   

This identified two distinct cancer groups among these patients.   

These two groups were then confirmed using two other mathematical approaches applied to different aspects of the data. And importantly, this finding was also validated in other independent datasets from Canada and Australia.   

The researchers were then able to integrate all of this information to generate an evolutionary tree showing how the two subtypes of prostate cancer develop, ultimately converging into two distinct ‘evotypes’.  

“This study is really important because until now, we thought that prostate cancer was just one type of disease. But it is only now, with advancements in artificial intelligence, that we have been able to show that there are actually two different subtypes at play,” said Professor Colin Cooper, from UEA’s Norwich Medical School.  

“We hope that the findings will not only save lives through better diagnosis and tailored treatments in the future, but they may help researchers working in other cancer fields better understand other types of cancer too.”  

Revolutionising the future of prostate cancer treatment

It’s hoped that these findings could revolutionise how prostate cancer is diagnosed and treated in the future.  

Crucially, the team’s collaboration with Cancer Research UK aims to develop a genetic test that, when combined with conventional staging and grading, can provide a more precise prognosis for each patient, allowing tailored treatment decisions.  

The work published today by this global consortium of researchers has the potential to make a real difference to people affected by prostate cancer. The more we understand about cancer the better chance we have of developing treatments to beat it.   We are proud to have helped fund this cutting-edge work, which has laid the foundations for personalised treatments for people with prostate cancer, allowing more people to beat their disease.

Prostate cancer is the most common cancer in men in the UK with around 55,000 cases a year. While prostate cancer is responsible for a large proportion of all male cancer deaths, it is more commonly a disease men die with rather than from. Research like this is key, as knowing when to avoid unnecessary treatment is also important, to help spare men from related side-effects such as incontinence and impotence.   

“We simply don’t know enough about what a prostate cancer diagnosis means at present – there are many men who have disease which is or may become aggressive and being able to treat aggressive disease more effectively is critical,” said Dr Naomi Elster, Director of Research at Prostate Cancer Research.  

“But on the other side of the coin are the too many men who live with side effects of cancer treatment they may never have needed.   

“These results could be the beginning of us being able to take the same ‘divide and conquer’ approach to prostate cancer that has worked in other diseases, such as breast cancer.”  

This feels like hugely important research. After diagnosis with prostate cancer early last year I went through a radical prostatectomy in July. After three quarterly blood tests my second and third have shown increased PSA levels. Whilst still virtually undetectable my consultant feels it important to bring me back for radiotherapy. That’s OK, but what about hormone therapy? Some research points to it not being necessary, other work shows that it’s more likely to finish off the cancer if you have a course of both. But at what cost in terms of side effects that affect your quality of life. Clarity at an earlier stage on how best to treat your disease has to be a good thing for all future prostate cancer patients.

It is excellent news – quite ground breaking? I believe that GP’s need to be less doubting than some currently are. Due to these doubts action is often delayed to the detriment of the patient, which is very worrying indeed. I hope things progress in this area. Thank you all who are tirelessly working on a solution for this cancer.

Working as a research nurse with men who are diagnosed with prostate cancer, PSA readings and scans if PSA results start to climb are still the best indicators for progression. I would agree that many men live with the disease, and eventually die of something else. The exception being those who are diagnosed younger with metastatic spread at diagnosis. Family history can suggest a hereditary risk.

This statement in your write-up resonates: “While prostate cancer is responsible for a large proportion of all male cancer deaths, it is more commonly a disease men die with rather than from.”

Just great news and progress. So pleased to have some good news. As a black man with a recent diagnosis of Prostate Cancer. I am super keen to read and learn as much about the disease. The two identified subtypes are so so interesting to me and I am sure many others. I wonder, how I can keep informed about the future of this research findings?

I have an aggressive prostate cancer and I found the information helpful.

This article is very interesting to me as a man and also an amateur medical student. Some years ago now there seemed to be great hope in using ensymes from red tomato skin to cure and possibly prevent prostrate cancer, with reports that tests had actually prove this theory, but there has since been no publicity about this.

And there’s Neuroendocrine Neoplasm of the prostate. Is this a third type or does it fit the model here?

Most are Neuroendocrine Carcinomas (I.e. poorly differentiated) but some are Neuroendocrine Tumours (I.e. well differentiated).

Hi Ronny, Thank you for your comment.

Neuroendocrine prostate cancer is a histological variant of prostate cancer, which is related to how the cancer cells look under a microscope.

But in this paper, the researchers are classifying the two subtypes based on the evolution of the disease, which can help to give clues about how the disease might progress as well as have implications for treatment.

It’s also worth noting that in this study they only examined samples from patients with intermediate or low risk prostate adenocarcinoma, which is the most common histological variant of prostate cancer. In their paper the authors do acknowledge that as this research is still in its early stages the findings may not be applicable to every prostate cancer case and there may be other evolutionary paths yet to be discovered.

I hope that helps, Amy, Cancer Research UK

What exactly are the two subtypes of prostate cancer ? The article does not say

Thanks for your comment.

The two evotypes identified in this research were named the ‘canonical’ and ‘alternative’ evotypes. These evotypes arise from what the researchers termed ‘divergent evolutionary trajectories’, meaning the tumours acquire different mutations to their DNA at different stages in their evolution.

Specifically, the ‘alternative’ evotype diverges from the ‘canonical’ evotype by acquiring mutations in genes that affect a protein called an androgen receptor.

I hope that helps, Jacob, Cancer Research UK

It’s really interesting from my perspective. Its good in the sense that my brother and I both have prostate cancer but different diagnosis. I’m 2 year older than him,he was diagnosed years before me,both have different life styles. Reading the articles are very informative.

Very promising research for the management of prostate cancer patients.

Tell us what you think

Leave a reply cancel reply.

Your email address will not be published. Required fields are marked *

Save my name, email, and website in this browser for the next time I comment.

Read our comment policy .

Highlighted content

Are ultra-processed foods linked to cancer, making cancer screening work for you, clearing the smoke on age of sale: the hidden tactics of the tobacco industry, that cancer conversation podcast – longer, better lives: ep.2 why did a doctor have to wait for her cancer treatment, what's it like to be diagnosed with cancer as a teenager, can vaping cause changes in our cells, flame of hope awards 2024: spotlight on our inspiring volunteers, related topics.

• Research and trials
• The Institute of Cancer Research
• Cancer in the news

April 16, 2024

10 min read

New Prostate Cancer Treatments Offer Hope for Advanced Cases

Major discoveries during the past 10 years have transformed prostate cancer treatment, enabling it to proceed even for the most advanced form of the disease

By Marc B. Garnick

David Cheney

D eciding how to diagnose and treat prostate cancer has long been the subject of controversy and uncertainty. A prime example involves prostate-specific antigen (PSA) testing, a blood test for a telltale protein that can reveal cancer even when the patient has no symptoms. After its introduction in the early 1990s, PSA testing was widely adopted—millions of tests are done in the U.S. every year. In 2012, however, a government task force indicated that this test can lead to overtreatment of cancers that might have posed little danger to patients and so might have been best left alone.

While arguments for and against PSA testing continue to seesaw back and forth, the field has achieved a better grasp on what makes certain prostate cancers grow quickly, and those insights have paved the way for better patient prognoses at every stage of the disease, even for the most advanced cases. A prostate cancer specialist today has access to an enhanced tool set for treatment and can judge when measures can be safely deferred.

The importance of these advances cannot be overstated. Prostate cancer is still one of the most prevalent malignancies. Aside from some skin cancers, prostate cancers are the most common cancers among men in the U.S. Nearly 270,000 people in America will be diagnosed with prostate cancer this year, and it is the fourth most common cancer worldwide. Fortunately, the vast majority of patients will live for years after being diagnosed and are more likely to die of causes unrelated to a prostate tumor.

On supporting science journalism

If you're enjoying this article, consider supporting our award-winning journalism by subscribing . By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today.

At its most basic level, prostate cancer is a malignancy that occurs in the prostate gland, which produces fluid that mixes with sperm from the testicles to make semen. The prostate is located in front of the rectum, below the bladder and above the penis, and cancer in the gland has four major stages.

Early on, localized tumors show no evidence of extension beyond the prostate gland. A second, “regionally advanced” form of the disease remains close to the prostate. Then there are metastatic prostate cancers, which spread outside the gland to other parts of the body. Treatment of tumors in this category has benefited from improved diagnostic imaging tests. In fact, with these tests, cancer specialists have characterized the fourth category, oligometastatic prostate cancer, a disease stage on a continuum between localized prostate cancer and more broadly dispersed metastatic disease. Major discoveries in the past 10 years have transformed the way we approach each type of prostate cancer, and these advances are likely to continue for decades to come.

The first treatment steps for people with localized cancer involve risk stratification. Through this process, a physician gauges the likelihood of a cancer’s being eliminated or cured by local treatment (usually surgery or radiation) and, if it does abate, of its returning. A physician determines the risk based on PSA results, physical examination of the prostate gland and inspection of cells from the biopsied tumor.

The right course of action for a patient with elevated PSA levels continues to undergo constant revision. Until five to seven years ago, a physician evaluated a person with high PSA by feeling their prostate gland for potentially cancerous abnormalities. Invariably, the next step would be a needle biopsy—an uncomfortable procedure in which the physician obtains snippets of prostate tissue through the rectum.

But we now have a way to biopsy through the perineum—the area between the back of the scrotum and the anal-rectal area. Thanks to technical improvements, it can be done in an outpatient setting without general anesthesia or sedation. The technique reduces the patient’s risk of infection and need for antibiotics because it doesn’t disrupt the bacterial flora in the rectum. In a recent study, researchers compared outcomes in patients who underwent a trans­rectal biopsy and received antibiotics with those for people who had a transperineal biopsy with minimal to no antibiotics. They found the two approaches comparable in terms of complications from infections.

Even more exciting is the prospect of eliminating biopsies altogether. When a patient has an abnormal PSA value but their rectal examination shows no obvious evidence of cancerous deposits, physicians can now use magnetic resonance imaging (MRI) to look at the prostate and surrounding tissue. MRI scans are best for identifying clinically significant cancers—those that, if left untreated or undiagnosed, could eventually spread. MRI can also uncover more extensive cancer spread or tumors in unusual locations such as the front of the prostate.

Another benefit of MRI procedures is that they identify fewer clinically insignificant cancers—those that are unlikely to cause problems and might best be left alone. In this case, failure to detect certain cancers is a good thing because it spares people unnecessary treatment. In some medical centers in the U.S. and many in Europe, a physician will perform a biopsy only if the MRI scan does reveal evidence of clinical significance. Studies that have compared the two diagnostic approaches—routine biopsy for all patients with elevated PSA levels versus biopsies based on abnormal MRI findings—found they are similarly effective at detecting clinically significant cancers.

Once a patient is diagnosed with prostate cancer, what happens next? For decades the debate over treatment has been just as contentious as the debate over diagnosis. Fortunately, new research from the U.K. has provided some clarity. Investigators there studied several thousand people with elevated PSA levels whose prostate biopsies showed cancer. These patients were randomized to receive surgical removal of the cancerous gland, radiation treatments or no active treatment at all. At the end of 15 years of comprehensive follow-up, about 3 percent of patients in each group had died of prostate cancer, and nearly 20 percent in each group had died of unrelated causes.

Based on the results of this study and others, more people are now being offered “active surveillance” after a prostate cancer diagnosis, in which treatment is either delayed or avoided altogether. Careful monitoring of patients who have not undergone surgery or radiation is becoming more common; it is now being extended even to those with more worrisome tumors. The monitoring involves a range of measures: PSA testing every three to six months, physical examination of the prostate gland and assessment of the patient’s urinary symptoms. Those tests are followed by repeat biopsies at increasing intervals, as long as there are no significant pathological changes.

If a cancer is identified as having either intermediate- or high-risk features, doctors need to track its progression, usually with bone scans using radio­­pharma­ceut­i­cals and with abdominal-pelvic computed tomography (CT) scans, which may show any spread in the areas to which prostate cancer most often metastasizes. Unfortunately, these techniques are not sensitive enough to reliably detect cancer in structures less than a centimeter in diameter, such as lymph nodes. Consequently, small areas of metastatic disease may go undetected. These cases are said to be “understaged.”

Understaging can now be studied through more precise diagnostic testing. Typically patients whose disease is understaged are not treated until the cancer becomes detectable through symptoms such as urination problems or pain. The disease then may require intensive therapies, and there is less of a chance of long-term remission. One technology that can help address understaging is advanced scanning that combines radiodiagnostic positron-emission tomography (PET) with CT.

These scans can detect molecules commonly found in prostate cancer cells, such as prostate-specific membrane antigen (PSMA). If PSMA is present outside the prostate gland, such as in pelvic lymph nodes, the affected areas can be identified, and a plan can be made for targeted radiation treatments or surgical removal.

Let’s consider how PET-CT scanning can be used in clinical practice. One of my patients, a 68-year-old man, was diagnosed with prostate cancer that was localized but had high-risk features. The traditional diagnostic bone and CT scans did not show any evidence of cancer spread outside the prostate. A PET-CT scan for PSMA, however, did reveal the presence of several small deposits of cancer cells in well-defined areas of the pelvis, indicating the cancer had spread to the lymph nodes. This finding prompted treatment that included radiation therapy in the prostate gland and the cancerous lymph nodes, as well as androgen-deprivation therapy (ADT), a treatment that reduces levels of testosterone, the hormone that enables prostate cancer to grow and progress.

The more precise identification of small tumor deposits in a limited number of pelvic lymph nodes—diagnosed as oligometastatic prostate cancer—enabled a new use for an old technology in oncology called metastasis-directed therapy (MDT), which targets cancer-containing lymph nodes or bony areas with radiation. At times, surgical removal of the abnormal lymph nodes may also be incorporated into MDT. Recently published studies on the use of MDT in conjunction with conventional treatments show, in some cases, long-term remission lasting through years of follow-up. Until recently, such a scenario was unthinkable for people whose prostate cancer had spread to their lymph nodes. My patient had the PSMA scan and MDT, as well as a relatively short course of ADT. He is cancer-free for now.

Precise identification of small metastatic deposits has other positive benefits. ADT has for decades been the mainstay for treating many forms of prostate cancer. Patients must continue the therapy for years, sometimes for the rest of their lives. Side effects of ADT are similar to those experienced during menopause. In fact, “andropause” is the term that captures the effects of ADT. Lower levels of testosterone are accompanied by a multitude of symptoms, including but not limited to loss of libido, erectile dysfunction, weight gain, hot flashes, bone loss, cognitive impairment, mood changes, diminished energy, and worsening of preexisting heart and vascular problems.

Studies of MDT for oligometastatic prostate cancer have raised the question of whether ADT could be delayed, administered for a shorter duration or even omitted in patients who otherwise would have required it. By strategically deploying traditional forms of localized treatment—usually surgery to remove the prostate gland or radiation—with added MDT for oligometastatic disease, doctors can significantly shorten the duration of ADT or potentially eliminate it. Such an approach would have been difficult to imagine five years ago. Longer-term follow-up studies will help scientists determine whether some people diagnosed in this fashion can go into an extended remission.

F or advanced forms of prostate cancer that have spread to other parts of the body, ADT has been the main treatment. Physicians historically have generally recommended surgical removal of the testicles—the primary source of testosterone—or the administration of other hormones that block the production and action of testosterone. In the mid-1980s I was involved with research on drugs called luteinizing hormone–releasing hormone analogues that lowered testosterone by shutting off the signal in the brain that instructs the testicles to make testosterone. Today newer agents have been added that further lower and block testosterone’s action.

The goal of prostate cancer treatment at later stages is to eliminate multiple sources of testosterone. As noted earlier, testosterone in the body comes predominantly from the testicles; the adrenal glands also produce a small amount. But prostate cancer cells can evolve to produce their own androgens. Testosterone and its active form, dihydrotestosterone (DHT), traverse the membranes of prostate cancer cells and interact with androgen receptors in the cytoplasm, a cell’s liquid interior. The receptors then transport DHT to the nucleus, where it instructs the cancer cell to grow, replicate and spread.

Traditional ADT does little to affect either the production of testosterone by the adrenal glands or androgen-producing prostate cancer cells, and it doesn’t block the activity of androgen receptors. But new approaches to ADT may address these shortcomings. Drug combinations that affect all these processes have substantially improved survival in people with metastatic prostate cancer—and, more important, patients are able to tolerate these more intensive treatment programs.

Instead of just one drug to decrease testosterone, new standards for treatment prescribe combinations of two or even three drugs. In addition to traditional ADT, there are medications such as do­cetaxel, a chemotherapy, and other new drugs that can block the production of testosterone by the adrenal glands or cancer cells or stop it by interfering with the activity of androgen receptors. All these drug combinations have resulted in meaningful improvements in survival.

Yet another therapy for advanced disease involves the identification of PSMA-expressing cancer cells that can be targeted with pharmaceuticals designed to deliver radioactive bombs. An injectable radiopharmaceutical can be delivered selectively to these cells, leaving healthy cells mostly unaffected. This therapy, lutetium-177-­PSMA-617 (marketed as Pluvicto), has been approved by the U.S. Food and Drug Administration for the treatment of prostate cancer that has become resistant to other forms of ADT and chemotherapy. It is likely to become an important therapy for even earlier stages of prostate cancer.

Genetics and genomic testing of patients and cancers have also helped in the quest for improvement of symptoms and longer survival. Some genetic mutations that are known to increase the risk of breast and ovarian cancer have also been associated with a heightened risk of prostate cancer. Testing for such mutations is becoming much more common, and patients who have them can be treated with specific therapies that block their deleterious effects, leading to better outcomes.

An understanding of the type of mutation is also critical—for both patients and their family members. Germline mutations are inherited from a patient’s biological parents by every cell in the body. These mutations can be passed along to the patient’s children. A somatic mutation, in contrast, is not inherited but develops in the cancer itself. Targeted therapies designed specifically to correct the effects of either germline or somatic mutations have produced significant improvements in patient longevity. Some of the most commonly recognized cancer mutations—either somatic or germline—are those in BRCA genes, which have been associated with early-onset breast and ovarian cancer.

When researchers studied cancer in families with BRCA mutations, they uncovered many cases of prostate cancer. This finding led to the discovery that BRCA mutations appeared in both men and women in these families. The mutations change the way DNA is repaired, introducing defects that can result in cancer formation. Drugs have now been developed that treat cancers linked to the BRCA mutations. Several such drugs—those in a class called poly­(ADP-ribose) polymerase (PARP) inhibitors—have recently received FDA approval for use as a treatment in people with these mutations. This research has led to more widespread genetic testing of patients with prostate cancer and, when germline mutations are found, family genetic counseling.

All these advances have occurred over the past decade—an incredibly short interval in the context of cancer oncology. Current options for early-stage prostate cancer enable physicians and patients to feel more at ease with conservative choices rather than immediate interventions with negative side effects. For patients whose cancers are advanced at initial diagnosis or progress and become metastatic, the treatment of oligometastases now often leads to long-term remission and requires fewer treatments with harmful systemic side effects. For those with more widespread metastatic disease, their cancer can now be managed with improved therapeutics based on a better understanding of disease biology. These new strategies have begun to transform this once rapidly fatal disease into a chronic condition that people can live with for years or even for their full life expectancy.

Marc B. Garnick is Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston. He is editor in chief of Harvard Medical School’s 2024–2025 Report on Prostate Diseases.

New urine-based test detects high-grade prostate cancer, helping men avoid unnecessary biopsies

The test looks at 18 genes and was specifically developed to pick out those cancers that need immediate treatment over the slow-growing type.

Researchers at the University of Michigan Rogel Cancer Center have developed a new urine-based test that addresses a major problem in prostate cancer: how to separate the slow-growing form of the disease unlikely to cause harm from more aggressive cancer that needs immediate treatment.

The test, called MyProstateScore2.0, or MPS2, looks at 18 different genes linked to high-grade prostate cancer. In multiple tests using urine and tissue samples from men with prostate cancer, it successfully identified cancers classified as Gleason 3+4=7 or Grade Group 2 (GG2), or higher. These cancers are more likely to grow and spread compared to Gleason 6 or Grade Group 1 prostate cancers, which are unlikely to spread or cause other impact. More than one-third of prostate cancer diagnoses are this low-grade form. Gleason and Grade Group are both used to classify how aggressive prostate cancer is.

Results are published in JAMA Oncology .

"Our standard test is lacking in terms of its ability to clearly pick out those who have significant cancer. Twenty years ago, we were looking for any kind of cancer. Now we realize that slow-growing cancer doesn't need to be treated. All of a sudden, the game changed. We went from having to find any cancer to finding only significant cancer," said co-senior study author John T. Wei, M.D., David A. Bloom Professor of Urology at Michigan Medicine.

Prostate-specific antigen, or PSA, remains the linchpin of prostate cancer detection. MPS2 improves upon a urine-based test developed by the same U-M team nearly a decade ago, following a landmark discovery of two genes that fuse to cause prostate cancer. The original MPS test, which is used today, looked at PSA, the gene fusion TMPRSS2::ERG, and another marker called PCA3.

"There was still an unmet need with the MyProstateScore test and other commercial tests currently available. They were detecting prostate cancer, but in general they were not doing as good a job in detecting high-grade or clinically significant prostate cancer. The impetus for this new test is to address this unmet need," said co-senior author Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology. Chinnaiyan's lab discovered the T2::ERG gene fusion and developed the initial MPS test.

To make MyProstateScore even stronger at identifying high-grade cancers, researchers used RNA sequencing of more than 58,000 genes and narrowed it to 54 candidates uniquely overexpressed specifically in higher-grade cancers. They tested the biomarkers against urine samples collected and stored at U-M through another major study, the National Cancer Institute's Early Detection Research Network. This included about 700 patients from 2008-2020 who came for a prostate biopsy due to an elevated PSA level.

This first step narrowed the field to 18 markers that consistently correlated with higher grade disease. The test still includes the original MPS markers, plus 16 additional biomarkers to complement them.

From there, the team reached out to the larger Early Detection Research Network (EDRN), a consortium of more than 30 labs across the country that are similarly collecting samples. This ensured a diverse, national sampling. Knowing no specific details about the samples, the U-M team performed MPS2 testing on more than 800 urine samples and sent results back to collaborators at the NCI-EDRN. The NCI-EDRN team assessed MPS2 results against the patient records.

MPS2 was shown to be better at identifying GG2 or higher cancers. More importantly, it was nearly 100% correct at ruling out GG1 cancer.

"If you're negative on this test, it's almost certain that you don't have aggressive prostate cancer," said Chinnaiyan, S. P. Hicks Endowed Professor of Pathology and professor of urology at Michigan Medicine.

Moreover, MPS2 was more effective at helping patients avoid unnecessary biopsies. While 11% of unnecessary biopsies were avoided with PSA testing alone, MPS2 testing would avoid up to 41% of unnecessary biopsies.

"Four of 10 men who would have a negative biopsy will have a low risk MPS2 result and can confidently skip a biopsy. If a man has had a biopsy before, the test works even better," Wei explained.

For example, a patient may get a prostate biopsy due to an elevated PSA, but no cancer is detected. The patient is followed over time and if his PSA inches up, he would typically need another biopsy.

"In those men who have had a biopsy before and are being considered for another biopsy, MPS2 will identify half of those whose repeat biopsy would be negative. Those are practical applications for patients out there. Nobody wants to say sign me up for another biopsy. We are always looking for alternatives and this is it," Wei said.

MPS2 is currently available through LynxDx, which is University of Michigan spin-off company that has an exclusive license from the university to commercialize MPS2. Patients interested in learning more can call the Michigan Medicine Cancer AnswerLine at 800-865-1125.

The paper's first authors are Jeffrey J. Tosoian, M.D., M.P.H., who is now at Vanderbilt University, and Yuping Zhang, Ph.D., and Lanbo Xiao, Ph.D., at U-M. Additional authors are Cassie Xie; Nathan L. Samora, M.D.; Yashar S. Niknafs, Ph.D.; Zoey Chopra; Javed Siddiqui; Heng Zheng, M.D.; Grace Herron; Neil Vaishampayan; Hunter S. Robinson, M.D.; Kumaran Arivoli; Bruce J. Trock, Ph.D.; Ashley E. Ross, M.D., Ph.D.; Todd M. Morgan, M.D.; Ganesh S. Palapattu, M.D.; Simpa S. Salami, M.D., M.P.H.; Lakshmi P. Kunju, M.D.; Scott A. Tomlins, M.D., Ph.D.; Lori J. Sokoll, Ph.D.; Daniel W. Chan, Ph.D.; Sudhir Srivastava, Ph.D.; Ziding Feng, Ph.D.; Martin G. Sanda, M.D.; Yingye Zheng, Ph.D.

Funding for this work is from the Michigan-Vanderbilt Early Detection Research Network Biomarker Characterization Center and Data Management and Coordinating Center, which are through the National Cancer Institute grants U2C CA271854 and U24 CA086368. Additional funding is from NCI grants P50 CA186786, R35 CA231996, U24 CA115102, U01 CA113913; Prostate Cancer Foundation; Howard Hughes Medical Institute; and the American Cancer Society.

Disclosures: Chinnaiyan serves on the advisory boards of Tempus, LynxDx, Ascentage Pharmaceuticals, Medsyn therapeutics, Esanik and RAAPTA therapeutics. Tomlins is an equity holder and chief medical officer of Strata Oncology. LynxDx has obtained an exclusive license from the University of Michigan to commercialize MPS2 and the TMPRSS2-ERG gene fusion. Tosoian and Chinnaiyan are equity holders and scientific advisers to LynxDx. Siddiqui, Zhang, Xiao and Niknafs have served as scientific advisers to LynxDx.

• Prostate Cancer
• Men's Health
• Prostate Health
• Breast Cancer
• Diseases and Conditions
• Colon Cancer
• Prostate cancer
• Breast cancer
• Colorectal cancer
• Cervical cancer
• Urinary incontinence
• Stem cell treatments
• Renal cell carcinoma

Story Source:

Materials provided by Michigan Medicine - University of Michigan . Original written by Nicole Fawcett. Note: Content may be edited for style and length.

Journal Reference :

• Jeffrey J. Tosoian, Yuping Zhang, Lanbo Xiao, Cassie Xie, Nathan L. Samora, Yashar S. Niknafs, Zoey Chopra, Javed Siddiqui, Heng Zheng, Grace Herron, Neil Vaishampayan, Hunter S. Robinson, Kumaran Arivoli, Bruce J. Trock, Ashley E. Ross, Todd M. Morgan, Ganesh S. Palapattu, Simpa S. Salami, Lakshmi P. Kunju, Scott A. Tomlins, Lori J. Sokoll, Daniel W. Chan, Sudhir Srivastava, Ziding Feng, Martin G. Sanda, Yingye Zheng, John T. Wei, Arul M. Chinnaiyan, Ian M. Thompson, Mohamed Bidair, Adam Kibel, Daniel W. Lin, Yair Lotan, Alan Partin, Samir Taneja, David H. Howard, Meredith M. Regan, Jack Groskopf, Jonathan Chipman, Dattatraya H. Patil, Douglas S. Scherr, Jacob Kagan, Jing Fan, Aron Y. Joon, Leonidas E. Bantis, Mark A. Rubin. Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer . JAMA Oncology , 2024; DOI: 10.1001/jamaoncol.2024.0455

Cite This Page :

Explore More

• New Circuit Boards Can Be Repeatedly Recycled
• Collisions of Neutron Stars and Black Holes
• Advance in Heart Regenerative Therapy
• Bioluminescence in Animals 540 Million Years Ago
• Profound Link Between Diet and Brain Health
• Loneliness Runs Deep Among Parents
• Food in Sight? The Liver Is Ready!
• Acid Reflux Drugs and Risk of Migraine
• Do Cells Have a Hidden Communication System?
• Mice Given Mouse-Rat Brains Can Smell Again

Trending Topics

Strange & offbeat.

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts

Prostate cancer articles within Nature Reviews Urology

In Brief | 16 April 2024

Patient-reported toxic effects of hypofractionated versus conventional RT

• Maria Chiara Masone

Perspective | 16 April 2024

Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers

Ferroptosis induction is a promising new therapeutic strategy for advanced prostate cancer. In this Perspective, the authors discuss the interplay between ferroptosis and metabolism. Current efforts to target ferroptosis and combination therapies in prostate cancer, as well as emerging methods to monitor this process in patients, are also discussed.

• Pham Hong Anh Cao
• , Abishai Dominic
•  &  Elavarasan Subramani

In Brief | 14 February 2024

ADT intensification to treat biochemically recurrent prostate cancer

Review Article | 02 February 2024

The complex interplay of modifiable risk factors affecting prostate cancer disparities in African American men

African American men are disproportionately affected by prostate cancer in the USA. In this Review, the authors discuss the complex interplay of modifiable risk factors that might underlie the glaring prostate cancer disparities observed.

• Jabril R. Johnson
• , Nicole Mavingire
•  &  Rick A. Kittles

Review Article | 02 January 2024

Shared decision-making before prostate cancer screening decisions

In this Review, the authors discuss shared decision-making for prostate cancer screening in terms of definition, prevalence and methods, including decision aids. Facilitators and barriers to shared decision-making are also discussed.

• Kelly R. Pekala
• , Daniela K. Shill
•  &  Sigrid V. Carlsson

Review Article | 19 December 2023

Intratumoural immunotherapy plus focal thermal ablation for localized prostate cancer

In this Review, the authors examine the potential synergy between thermal ablation and intratumoural immunotherapy in treating localized prostate cancer. This combination could transform the traditionally cold immunological landscape of prostate cancer into a hot one, enhancing treatment efficacy.

• Denis Séguier
• , Eric S. Adams
•  &  Thomas J. Polascik

Review Article | 14 November 2023

Genetic and biological drivers of prostate cancer disparities in Black men

Genetic and ancestral factors, molecular pathways involving androgen and non-androgen receptor signalling, inflammation, epigenetics, the tumour microenvironment and tumour metabolism are posited as biological factors that potentially contribute to racial disparities in Black men with prostate cancer.

• , Daniel M. Kim
•  &  Stephen J. Freedland

Review Article | 31 October 2023

Prognostic and therapeutic potential of senescent stromal fibroblasts in prostate cancer

Senescent stromal fibroblasts exhibit a senescence-associated secretory phenotype, which can promote prostate cancer development, progression and resistance to therapy. Targeting senescent cells via senotherapeutics might be an attractive preventive or therapeutic option for prostate cancer.

• Joakin O. Mori
• , Isra Elhussin
•  &  Christopher M. Heaphy

Research Highlight | 11 September 2023

Feasibility and potential of an MRI-based prostate cancer screening

Research Highlight | 08 September 2023

A fully transperineal approach for prostate biospy

News & Views | 30 August 2023

PSMA-targeted fluorescence guidance for robotic-assisted prostatectomy

Positive surgical margins are an independent risk factor for biochemical recurrence after radical prostatectomy. However, the identification of residual cancer by eye is highly limited, and frozen sections are not always available or possible for all margins. Prostate-specific membrane antigen-targeted fluorescence guidance might close this gap and enhance the surgeon’s eye.

• Fabian Falkenbach
•  &  Tobias Maurer

Review Article | 21 August 2023

Bioinformatics in urology — molecular characterization of pathophysiology and response to treatment

In this Review, the authors provide an overview of the main bioinformatics tools available for urologists. The main applications of bioinformatics in the field of urological oncology, as well as in benign urological disease, are discussed, with a special focus on molecular characterization of disease physiopathology and response to treatment. Challenges and future perspectives in the field are also discussed.

• Ali Hashemi Gheinani
•  &  Rosalyn M. Adam

Research Highlight | 08 August 2023

New insights into APOBEC-mediated mutagenesis in prostate cancer

In Brief | 08 August 2023

Nicardipine inhibits chemoresistance in prostate cancer

Tuft cells in prostate cancer, platin-l improves cisplatin resistance.

Perspective | 25 July 2023

The potential role of the microbiota in prostate cancer pathogenesis and treatment

The microbiota influences the body in homeostasis and disease, including cancer, and, although specific urinary and gut microbial species have been associated with an increased risk of prostate cancer, causal mechanistic data remain elusive. In this Perspective article, the authors discuss the roles of the microbiota in prostate carcinogenesis and progression, and consider how these might be leveraged for diagnosis and treatment of the disease.

• Nicolò Pernigoni
• , Christina Guo
•  &  Andrea Alimonti

Research Highlight | 10 July 2023

Metabolic alterations drive enzalutamide resistance

Parp inhibitors plus enzalutamide to treat mcrpc.

Review Article | 22 May 2023

Sexual health and treatment-related sexual dysfunction in sexual and gender minorities with prostate cancer

Effects of prostate cancer treatment in sex and gender minority groups, which include gay and bisexual men, transgender women, or transfeminine people, can include altered sexual function in relation to receptive anal and neovaginal intercourse and changes to patients’ role-in-sex, as well as changes in sexual pleasure related to the loss of the prostate as a source of sexual pleasure. In this Review, the authors discuss the prostate as a sexual organ and consider the effects of prostate cancer treatment in patients from these under-represented groups, as well as discussing the need for openness and counselling in patients from sexual and gender minorities.

• Daniel R. Dickstein
• , Collin R. Edwards
•  &  Deborah C. Marshall

Review Article | 17 May 2023

Obesity and prostate cancer — microenvironmental roles of adipose tissue

Current evidence suggests that adipose stromal cells, a component of peri-prostatic white adipose tissue and the tumour microenvironment, have an important role in driving aggressive prostate cancer in obesity. These cells are potential targets of therapies to suppress cancer aggressiveness in obesity.

• Achinto Saha
• , Mikhail G. Kolonin
•  &  John DiGiovanni

Research Highlight | 21 April 2023

PROTACs for prostate cancer

• Louise Stone

Comment | 03 April 2023

Patient preferences in the treatment of genitourinary cancers

Several newly approved therapies have substantially altered the treatment paradigm for multiple genitourinary cancers. Considering the existence of numerous possible treatment approaches, understanding which treatment attributes are most valued by each patient is crucial to physicians to recommend a cancer-directed treatment.

• David J. Benjamin
•  &  Arash Rezazadeh Kalebasty

Consensus Statement | 03 April 2023

Unanswered questions in prostate cancer — findings of an international multi-stakeholder consensus by the PIONEER consortium

In this Consensus Statement, the authors present results from an international multi-stakeholder consensus conducted by the PIONEER consortium to identify the most important questions in the field of prostate cancer that could be addressed using big data.

• Muhammad Imran Omar
• , Steven MacLennan
•  &  Daniel Kotik

Review Article | 24 March 2023

Calcium signalling pathways in prostate cancer initiation and progression

In this Review, the authors provide an overview of the role of calcium as a driver of prostate cancer onset and progression, and discuss the most current therapies targeting the calcium signalling machinery to treat this malignancy.

• Roberto Silvestri
• , Vanessa Nicolì
•  &  Martin D. Bootman

Research Highlight | 16 March 2023

Singling out the immune-suppressive TME in prostate cancer

Rucaparib improves pfs in patients with brca1/2 -altered mcrpc.

Research Highlight | 14 March 2023

The role of GALNT7 as a potential diagnostic marker in prostate cancer

Pi5p4kα: a target in prostate cancer.

Research Highlight | 10 March 2023

Detecting lymph node metastases for personalized radiotherapy in patients with prostate cancer

Review Article | 14 February 2023

Preclinical models of prostate cancer — modelling androgen dependency and castration resistance in vitro, ex vivo and in vivo

Prostate cancer depends on the hormonal environment for growth. In this Review, the authors describe how this hormonal dependency can be studied in preclinical models. Advantages and limitations of these models are discussed to maximize the transfer of knowledge from scientific research to clinical applications.

• Lucas Germain
• , Camille Lafront
•  &  Étienne Audet-Walsh

Research Highlight | 13 February 2023

GHR expression and prostate cancer proliferation

In Brief | 10 February 2023

PARP inhibitor response in prostate cancer

Metabolic flexibility in ccrcc, immunoproteasome inhibition in crpc.

Research Highlight | 07 February 2023

CMA mediates resistance to androgen inhibitors in prostate cancer

Prostate cancer care for american indians and alaska natives.

Perspective | 17 January 2023

The future of patient-derived xenografts in prostate cancer research

This Perspective covers existing patient-derived xenografts (PDXs) of prostate cancer, and their features and uses in basic and preclinical research. The authors also discuss the need for additional PDXs, and how collaboration in prostate cancer PDX research can be improved.

• Mitchell G. Lawrence
• , Renea A. Taylor
•  &  Gail P. Risbridger

Research Highlight | 11 January 2023

Can systematic biopsy be omitted from the prostate cancer diagnostic pathway?

Research Highlight | 05 January 2023

Modelling AR mutations

In Brief | 04 January 2023

Irreversible electroporation in radio-recurrent prostate cancer

Arbs heterogeneity in prostate cancer progression, cribriform morphology affects mpmri imaging.

Review Article | 04 January 2023

Prostate cancer risk, screening and management in patients with germline BRCA1/2 mutations

Mutations in the BRCA1 and BRCA2 tumour suppressor genes are associated with prostate cancer risk, but optimal screening protocols for individuals with these mutations have been a subject of debate. In this Review, the authors discuss the risk associated with BRCA 1/2 mutations and consider how, and whether, a screening programme should be implemented for these individuals.

• Pawel Rajwa
• , Fahad Quhal
•  &  Shahrokh F. Shariat

Research Highlight | 21 December 2022

MRI diagnosis and radical prostatectomy outcomes

Perspective | 12 December 2022

Combination treatment in metastatic prostate cancer: is the bar too high or have we fallen short?

Combination treatment with androgen deprivation therapy plus chemotherapy or novel hormonal agents showed promising results for the treatment of patients with newly diagnosed metastatic prostate cancer. However, real-world data show a very low uptake of this therapy in clinical practice. In this Perspective, the authors discuss data and potential reasons behind this trend.

• Kenneth Chen
• , Jonathan O’Brien
•  &  Arun A. Azad

In Brief | 08 December 2022

Tumour-suppressing HIIT serum

Research Highlight | 07 December 2022

FOXA2–KIT-driven lineage plasticity in NEPC

Perspective | 23 November 2022

Relationships between holmium laser enucleation of the prostate and prostate cancer

In this Perspective, the authors present clinical scenarios in which prostate hyperplasia and prostate cancer overlap, with a specific focus on holmium laser enucleation of the prostate (HoLEP). Variables associated with incidental prostate cancer detection at HoLEP and prostate cancer development after HoLEP, as well as the role of HoLEP in patients with biopsy-proven prostate cancer, are also discussed.

• Matthew S. Lee
• , Mark A. Assmus
•  &  Amy E. Krambeck

In Brief | 31 October 2022

WGC in patients with localized prostate cancer

Browse broader subjects

• Prostatic diseases
• Urological cancer

Alpha-emitters based therapy prolongs life for patients with advanced prostate cancer

Novel therapy used in an ongoing Phase I clinical study shows substantial antitumour effect in patients with metastatic castration-resistant prostate cancer (mCRPC), with no serious adverse side-effects.

A Targeted Alpha Therapy initiated at the JRC and then further developed with the University Hospital Heidelberg – using Actinium-225 (²²⁵Ac) prostate-specific membrane antigen (PSMA) – represents a viable therapy option in patients treated with previous lines of approved agents, according to a JRC co-authored study in the Lancet Oncology medical journal.

For patients with metastatic castration-resistant prostate cancer (mCRPC) – the lethal form of prostate cancer progression – this emerging research suggests that actinium-225 (²²⁵Ac) prostate-specific membrane antigen (PSMA) radioligand therapy may have a significant impact in reducing prostate-specific antigen (PSA) levels and bolstering progression-free and overall survival rates.

In this study, researchers examined data from 488 patients between 2016 and 2023, treated at seven clinical centres across Australia, India, Germany, and South Africa. It is the largest investigation of the antitumor effect and toxicity of 225Ac-PSMA to date. This radioligand therapy has substantial antitumor effects in metastatic prostate cancer with very limited side effects. Prospective trials are needed to validate the safety and survival benefits of 225Ac-PSMA therapy in patients with this type of cancer.

For the analysed period, the study reports median overall survival of 15.5 months and median progression-free survival of 7.9 months.

The results stem from an international collaboration on Targeted Alpha Therapy (TAT), as promising novel approach to cancer therapy. If delivered directly to cancerous tissue by a targeting vehicle, the alpha particles kill tumour cells while minimising side effects to surrounding healthy organs. The JRC is a pioneer in R&D of alpha-emitters in oncology, supporting the development of therapies which target specific tumour cells and address micro-metastases of various cancer types. It supports hospitals and cancer centres in establishing the capabilities to offer Targeted Alpha Therapy treatment to cancer patients.

Under the  Europe’s Beating Cancer Plan , third countries benefit directly from the actions through collaborative research within the framework of Horizon Europe , the EU’s research funding programme. The result of the Lancet Oncology study mainly stems from the collaboration between the Steve Biko Academic Hospital (SBAH) and the JRC, initiated by two experts, Prof Mike Sathekge and Alfred Morgenstern.

This cooperation has built capacity for Targeted Alpha Therapy activity in Africa to treat cancer, particularly prostate cancer patients. SBAH has become a TAT training hub for knowledge dissemination to physicians from neighbouring countries. The unique capability and experience in applying TAT to African patients available at SBAH has led to the SBAH becoming the world first controlled Phase I clinical study site on the evaluation of 225Ac-PSMA in prostate cancer patients, conducted in collaboration with the JRC and the pharmaceutical industry.

In 2013-2014 the JRC together with University Hospital Heidelberg achieved a breakthrough with the development of 225Actinium-PSMA617 for treatment of prostate cancer. The two hold a patent on the drug and related compounds.

Since 2014 the novel compound has been tested clinically and provided to prostate cancer patients through collaboration of JRC scientists based in Karlsruhe with hospitals in Heidelberg, Munich and Pretoria among others. Due to the remarkable therapeutic efficacy of Ac-PSMA for the treatment of prostate cancer, its clinical use has rapidly been implemented worldwide and a prospective Phase I study is underway to move the compound to regulatory approval.

In the frame of the collaboration with the Steve Biko hospital in South-Africa, the JRC trained hospital personnel, implemented in-house developed protocols for safe handling of alpha emitters in clinical settings, supported installation of laboratory equipment and provided guidance for patient treatment with 225Ac-PSMA617 and related compounds.

The JRC is also supplying the alpha emitter Actinium-225 for clinical application. Through this collaboration, to date, more than 300 South African prostate cancer patients have been successfully treated, often with life-saving results.

The development of Ac-PSMA has won the 2017 Marie Curie Award of the European Association of Nuclear Medicine.

Related links

Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study

• Cancer and non-communicable diseases
• Health crises responses

More news on a similar topic

• News announcement
• 17 April 2024

• Supplementary information
• 16 April 2024

• 9 February 2024

• 31 January 2024

Share this page

Skip to Content

• Conquer Cancer
• ASCO Journals
• f Cancer.net on Facebook
• t Cancer.net on Twitter
• q Cancer.net on YouTube
• g Cancer.net on Google

Types of Cancer

• Navigating Cancer Care
• Coping With Cancer
• Research and Advocacy
• Survivorship

Prostate Cancer: Latest Research

ON THIS PAGE: You will read about the scientific research being done to learn more about prostate cancer and how to treat it. Use the menu to see other pages.

Doctors are working to learn more about prostate cancer, ways to prevent it, how to best treat it, and how to provide the best care to people diagnosed with this disease. The following areas of research may include new options for patients through clinical trials. Always talk with your doctor about the best diagnostic and treatment options for you.

Finding causes of prostate cancer. Researchers continue to explore the link between nutrition and other lifestyle factors and the development of prostate cancer.

Early detection. Researchers are trying to develop a better prostate-specific antigen (PSA) test, either a more specific and precise test or a different test. With improved testing, more healthy people could be screened for prostate cancer, so more prostate cancers could be found and treated early.

Genomic tests. Genomics is the study of how genes behave. Genomic tests look at the genes in prostate cancer to help predict how quickly the cancer may grow and spread. The information from these tests can help the cancer care team make decisions about the treatment plan, such as whether active surveillance is an option for those with low-risk prostate cancer or by helping the health care team make a prognosis after surgery and choose the best adjuvant treatments. Some of the genomic tests available now include Decipher, Oncotype DX, ProstaVysion, and the Prolaris Test.

The National Comprehensive Cancer Network (NCCN) recently updated their guidelines to include details about genomic testing in prostate cancer. They recommend that people with metastatic castration-resistant prostate cancer receive testing for inherited and tumor mutations, which could help direct treatment. 

Learn more about ASCO recommendations for genomic tests for prostate cancer in the Diagnosis  section.

Advanced imaging scans. Research is ongoing to use different molecules in PET-CT scans (positron-emission tomography, computed tomography; see Diagnosis ) to gather important information about a prostate cancer diagnosis, such whether there is distant spread (metastasis).

Improved surgical techniques. Better techniques for nerve-sparing surgery can decrease the risk of urinary and sexual side effects for people who need a radical prostatectomy.

Shorter radiation therapy schedules. With better, more precise external-beam radiation therapy, researchers are exploring much shorter and more convenient treatment schedules. Instead of 40 treatments, researchers are evaluating using 28, 12, or 5 treatments instead.

Tests to evaluate the success of treatment. Research continues to evaluate biomarkers that are found in the blood. These biomarkers can help determine the effectiveness of a treatment and be used to better assess the cancer’s response to treatment. Blood tests measuring circulating tumor cells (CTCs) are 1 such test. CTCs are cells that have broken free from the tumor.

Improved therapy for advanced prostate cancer. Researchers are exploring different treatment options for advanced prostate cancer in clinical trials, including special targeted drugs, chemotherapy, hormonal therapy, immunotherapy, and combinations of different types of therapies.

Palliative care/supportive care. Clinical trials are underway to find better ways of reducing symptoms and side effects of current prostate cancer treatments to improve comfort and quality of life for patients.

Looking for More About the Latest Research?

If you would like more information about the latest areas of research in prostate cancer, explore these related items that take you outside of this guide:

To find clinical trials specific to your diagnosis, talk with your doctor or search online clinical trial databases .

Visit the Cancer.Net Blog to review research in prostate cancer, including the 2022 Genitourinary Cancers Symposium and 2021 ASCO Annual Meeting , and to listen to podcasts with experts in the field discussing recent research.

Visit the website of Conquer Cancer, the ASCO Foundation , to find out how to help support cancer research. Please note that this link takes you to a different ASCO website.

The next section in this guide is Coping with Treatment . It offers some guidance on how to cope with the physical, emotional, social, and financial changes that cancer and its treatment can bring. Use the menu to choose a different section to read in this guide.

Prostate Cancer Guide

Cancer.Net Guide Prostate Cancer

• Introduction
• Medical Illustrations
• Risk Factors and Prevention
• Symptoms and Signs
• Stages and Grades
• Types of Treatment
• About Clinical Trials
• Latest Research
• Coping with Treatment
• Follow-Up Care
• Questions to Ask the Health Care Team
• Additional Resources

View All Pages

Timely. Trusted. Compassionate.

Comprehensive information for people with cancer, families, and caregivers, from the American Society of Clinical Oncology (ASCO), the voice of the world's oncology professionals.

Find a Cancer Doctor

• Alzheimer's disease & dementia
• Arthritis & Rheumatism
• Attention deficit disorders
• Autism spectrum disorders
• Biomedical technology
• Diseases, Conditions, Syndromes
• Endocrinology & Metabolism
• Gastroenterology
• Gerontology & Geriatrics
• Health informatics
• Inflammatory disorders
• Medical economics
• Medical research
• Medications
• Neuroscience
• Obstetrics & gynaecology
• Oncology & Cancer
• Ophthalmology
• Overweight & Obesity
• Parkinson's & Movement disorders
• Psychology & Psychiatry
• Radiology & Imaging
• Sleep disorders
• Sports medicine & Kinesiology
• Vaccination
• Breast cancer
• Cardiovascular disease
• Chronic obstructive pulmonary disease
• Colon cancer
• Coronary artery disease
• Heart attack
• Heart disease
• High blood pressure
• Kidney disease
• Lung cancer
• Multiple sclerosis
• Myocardial infarction
• Ovarian cancer
• Post traumatic stress disorder
• Rheumatoid arthritis
• Schizophrenia
• Skin cancer
• Type 2 diabetes
• Full List »

share this!

April 27, 2024

This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

peer-reviewed publication

trusted source

Component of keto diet plus immunotherapy may reduce prostate cancer

by Deanna Csomo Ferrell, University of Notre Dame

Adding a pre-ketone supplement—a component of a high-fat, low-carb ketogenic diet—to a type of cancer therapy in a laboratory setting was highly effective for treating prostate cancer, researchers from the University of Notre Dame found.

Recently published online in the journal Cancer Research , the study from Xin Lu, the John M. and Mary Jo Boler Collegiate Associate Professor in the Department of Biological Sciences, and collaborators tackled a problem oncologists have battled: Prostate cancer is resistant to a type of immunotherapy called immune checkpoint blockade (ICB) therapy. ICB therapy blocks certain proteins from binding with other proteins and paves the way for our body's fighter cells, T cells, to kill the cancer.

"Prostate cancer is the most common cancer for American men, and immunotherapy has been really influential in some other cancers, like melanoma or lung cancer , but it hasn't been working almost at all for prostate cancer," said Lu, who is affiliated with the Boler-Parseghian Center for Rare and Neglected Diseases. Adding a dietary supplement might overcome this resistance, the lead author in the study, Sean Murphy, suggested.

Murphy, a '24 alumnus who was a doctoral student in Lu's lab, had been following a keto diet himself. Knowing that cancer cells feed off of sugar, he decided that depriving mouse models of carbohydrates—a key component of the keto diet—might prevent cancer growth.

He divided the models into different groups: immunotherapy alone, ketogenic diet alone, a pre-ketone supplement alone, the ketogenic diet with the immunotherapy, the supplement with the immunotherapy, and the control. While the immunotherapy alone had almost no effect on the tumors (just like what happens to most patients with prostate cancer), both the ketogenic diet with the immunotherapy and the pre-ketone supplement with the immunotherapy reduced the cancer and extended the lives of the mouse models.

The supplement with the immunotherapy worked best.

"It turned out this combination worked really well," Lu said. "It made the tumor become very sensitive to the immunotherapy, with 23 percent of the mice cured—they were tumor-free; in the rest, the tumors were shrinking really dramatically."

The evidence points to the possibility that a supplement providing ketones, which are what is produced in the body when people eat a keto diet, might prevent the prostate cancer cells from being resistant to immunotherapy. This may lead to future clinical studies that examine how ketogenic diets or keto supplements could enhance cancer therapy.

While keto diets allow for minimal carbohydrates, the success of this study is not about the lack of carbohydrates, Murphy and Lu stressed. It is about the presence of the ketone body, a substance produced by the liver and used as an energy source when glucose is not available. The ketones disrupt the cycle of the cancer cells, allowing the T cells to do their job to destroy them.

The discovery was also exciting on a molecular level, Lu said. Any type of dietary study can suffer from the potential issue of causation: Are the results from the diet or other changes made because of the diet? But Lu and his collaborators confirmed their results using single-cell RNA sequencing, which examines the gene expression of single cells within the tumor.

"We found that this combination of the supplement and the immunotherapy reprogrammed the whole immune profile of the tumors and recruited many T cells into the tumors to kill prostate cancer cells," Lu said.

The successful therapy also reduced the number of a type of immune cell called neutrophils. Once in the tumor microenvironment , neutrophils' natural properties become greatly distorted, and they become largely responsible for inhibiting T cell activities and allowing more tumor progression. Dysregulation of neutrophils is also associated with many other diseases.

"With the main ketone body depleting neutrophils, it opens the door for investigating the effects of the keto diet and the ketone supplement on diseases ranging from inflammatory bowel disease to arthritis," Murphy said.

"What's exciting is that we're getting closer to the mechanism, backed up by genetic models and what we're seeing in the tumors themselves, of why this works," he said.

Co-authors include Sharif Rahmy, Dailin Gan, Guoqiang Liu, Yini Zhu, Maxim Manyak, Loan Duong, Jianping He, James H. Schofield, Zachary T. Schafer, Jun Li and Xuemin Lu, all from the University of Notre Dame.

Explore further

Feedback to editors

Research shows 'profound' link between dietary choices and brain health

16 hours ago

Study finds big jump in addiction treatment at community health clinics

20 hours ago

Positive childhood experiences can boost mental health and reduce depression and anxiety in teens

Gene linked to epilepsy and autism decoded in new study

Apr 26, 2024

Blood test finds knee osteoarthritis up to eight years before it appears on X-rays

Researchers find pregnancy cytokine levels impact fetal brain development and offspring behavior

Study finds biomarkers for psychiatric symptoms in patients with rare genetic condition 22q

Clinical trial evaluates azithromycin for preventing chronic lung disease in premature babies

Scientists report that new gene therapy slows down amyotrophic lateral sclerosis disease progression

Using stem cell-derived heart muscle cells to advance heart regenerative therapy

Related stories.

Genetically engineered dendritic cells enhance the power of immunotherapy against lung cancer

Mar 26, 2024

For metastatic prostate cancer, immunotherapy may have unexpected potential

Dec 12, 2023

Targeted immunotherapy could lead to pioneering treatment for breast cancer

Feb 29, 2024

New prostate cancer treatment concept

Aug 26, 2019

Exposing cancers to bacteria reminds first responder immune cells which side they're on

Mar 13, 2023

Targeting cancer-supporting cells boosts immunotherapy in previously insensitive tumors

Jan 9, 2023

Recommended for you

Study identifies driver of liver cancer that could be target for treatment

Analysis identifies 50 new genomic regions associated with kidney cancer risk

Biomarkers identified for successful treatment of bone marrow tumors

New research sheds light on the weakening immune response observed in older adults

How the immune system learns from harmless particles

Let us know if there is a problem with our content.

Use this form if you have come across a typo, inaccuracy or would like to send an edit request for the content on this page. For general inquiries, please use our contact form . For general feedback, use the public comments section below (please adhere to guidelines ).

Please select the most appropriate category to facilitate processing of your request

Thank you for taking time to provide your feedback to the editors.

Your feedback is important to us. However, we do not guarantee individual replies due to the high volume of messages.

E-mail the story

Your email address is used only to let the recipient know who sent the email. Neither your address nor the recipient's address will be used for any other purpose. The information you enter will appear in your e-mail message and is not retained by Medical Xpress in any form.

Newsletter sign up

Get weekly and/or daily updates delivered to your inbox. You can unsubscribe at any time and we'll never share your details to third parties.

More information Privacy policy

Donate and enjoy an ad-free experience

We keep our content available to everyone. Consider supporting Science X's mission by getting a premium account.

E-mail newsletter

More From Forbes

Former nih director francis collins has prostate cancer. use his story to reduce your risk of dying of this disease.

• Share to Facebook
• Share to Twitter
• Share to Linkedin

Francis Collins, April 2, 2013 in the East Room of the White House in Washington, DC. MANDEL ... [+] NGAN/AFP via Getty Images

Dr. Francis Collins revealed that he has prostate cancer, and that it recently transformed into a larger, more aggressive cancer. Why did he share this personal news? Because he wants to share lifesaving information about prostate cancer , the most common cancer and the #2 cause of cancer death among men in the United States.

Dr. Collins served as the director of the National Institutes of Health from 2009 to 2021. But genetics geeks, like myself, remember him as the director of the National Human Genome Research Institute from 1993 to 2008, during which time the human genome was sequenced . This accomplishment was one of the greatest medical breakthroughs of our generation. And its promise is still unfolding twenty years later, with new tests, discoveries, and precision medicines being developed based on genomic technologies.

There is an opportunity for some men who discover their prostate cancer at an early stage to consider ‘active surveillance’ instead of more radical, traditional approaches. For some men with an inherited form of prostate cancer, such as those with a BRCA2 mutation, the cancer may be more aggressive. For these men, ‘active surveillance’ may not be the recommended course of action.

What can the average person take away from Dr. Collins’ story and the risk of prostate cancer?

· Prostate cancer is common, with 1 in 8 men developing the disease over their lifetime.

· Prostate cancer does not have to be a death sentence. Many men with prostate cancer will live with the disease and die of something else.

The Best Romantic Comedy Of The Last Year Just Hit Netflix

Apple iphone 16 unique all new design promised in new report, rudy giuliani and mark meadows indicted in arizona fake electors case.

· By age 45, everyone with a prostate gland should discuss their risk of prostate cancer and the pros and cons of prostate screening with their clinician, as well as the recommended age to consider screening.

· Men with a family history of the disease, and African American men, should consider screening by age 45. If you have a family history of prostate cancer that includes a close relative diagnosed before age 55, consider screening 10 years earlier than the first prostate cancer diagnosis in your family. If you carry a BRCA2 mutation, screening should begin by age 40.

· Every person should research and document their family history of cancer. Share this information with your family members and keep a copy of this information with your other vital records.

· Your cancer family history should include both sides of your family, the age of diagnosis of each cancer, and not only prostate cancer, but every type of cancer.

· In addition to having relatives with prostate cancer, other things in your family history can increase your risk of prostate cancer, including:

o A family history of breast, ovary, fallopian tube, and/or pancreas cancer in close relatives;

§ Cancers diagnosed at an early age increase the risk of an underlying hereditary

o Jewish and/or African ancestry;

o A history of a known BRCA1 or BRCA2 mutation;

o A BRCA1 or BRCA2 mutation found in tumor tissue (prostate or other).

Prostate Cancer and Genetic Testing

· If you are concerned about your personal risk of prostate (or other) cancer, speak to a certified genetic counselor . If there is not a genetic counselor near you, you can speak to one by phone or telehealth. That genetic counselor can help assess your risk and determine if you are a candidate for genetic testing.

Dr. Collins helped bring us the core genetics knowledge that is driving precision medicine forward, to advance medical care. He has now shared his personal story to help others receive the same level of medical treatment he has accessed. Indeed, there is great hope for people diagnosed with prostate cancer today. Thank Dr. Collins by taking full advantage of this knowledge, researching your family history, and speaking to a certified genetic counselor about whether you and/or family members qualify for genetic testing.

Many thanks to Beth N. Peshkin, MS, CGC for her thoughtful review and edits.

• Editorial Standards
• Reprints & Permissions

• HEALTH & FITNESS

Focused therapy cuts side effects in treating prostate cancer

Defense Secretary Lloyd Austin's medical issues last December put the spotlight on fighting prostate cancer while reducing the risk of side effects and complications.

A trial here on a less invasive technique seems to point the way to keep cancer at bay while maintaining a quality of life.

For a decade, prostate cancer has been on the rise, and the incidence is expected to increase even more by 2050.

While it doesn't always endanger men's lives, it can affect their quality of life with incontinence or sexual dysfunction.

Dr. Andres Correa, a urologic oncologist at Fox Chase Cancer Center, says treating the whole prostate when the cancer is isolated raises those risks.

"The goal of focal therapy is to identify those patients that have cancer in a specific place that we can see on the MRI," says Dr. Correa.

Fox Chase has been in nationwide tests of the Nanoknife focal therapy, which uses IRE, an electrical technique, to destroy a tumor, yet leave healthy tissue alone.

So far, no one treated with Nanoknife has had cancer return on that side.

"No patients has had any incontinence," says Dr. Correa.

And any sexual issues have been short-lived.

"After like 6 months or so it seems to be able to wean off the medications," he says.

Dr. Correa says another therapy - high-intensity focused ultrasound or HIFU - is becoming a bigger part of the procedures done at Fox Chase.

"HIFU uses focused ultrasound to hit the tissue, to create that ablation or that destruction of tissue," he explains.

Cryoablation, which uses extreme cold, is a third focal therapy.

The size and location of the cancer determine which is best.

"If you have a large tumor, cryo is probably better than IRE just because it allows you to treat, to get a better, a better treatment zone," he notes.

He urges men to take time to find out what's best for them.

"It's important for someone not to go to the center that just provides one, but a kind of 2 or 3 different tools that can mold to the patient's anatomy and where the cancer is located," says Dr. Correa.

Treatments are evolving quickly, as doctors realize that quality of life is as important as a cure.

"Prostate could be treated very differently in 10 years than it's treated now," he predicts.

Fox Chase now has a Voorhees, New Jersey, office so men in South Jersey can get some of their care closer to home.

Related Topics

• MOVES IN MEDICINE FCCC

• International edition
• Australia edition
• Europe edition

‘Real hope’ for cancer cure as personal mRNA vaccine for melanoma trialled

Excitement among patients and researchers as custom-built jabs enter phase 3 trial

Doctors have begun trialling in hundreds of patients the world’s first personalised mRNA cancer vaccine for melanoma, as experts hailed its “gamechanging” potential to permanently cure cancer.

Melanoma affects about 132,000 people a year globally and is the biggest skin cancer killer. Currently, surgery is the main treatment although radiotherapy, medicines and chemotherapy are also sometimes used.

Now experts are testing new jabs that are custom-built for each patient and tell their body to hunt down cancer cells to prevent the disease ever coming back.

A phase 2 trial found the vaccines dramatically reduced the risk of the cancer returning in melanoma patients. Now a final, phase 3, trial has been launched and is being led by University College London Hospitals NHS Foundation Trust (UCLH).

Dr Heather Shaw, the national coordinating investigator for the trial, said the jabs had the potential to cure people with melanoma and are being tested in other cancers, including lung, bladder and kidney.

“This is one of the most exciting things we’ve seen in a really long time,” said Shaw. “This is a really finely honed tool. To be able to sit there and say to your patients that you’re offering them something that’s effectively like the Fat Duck at Bray versus McDonald’s – it’s that level of cordon bleu that’s coming to them … The patients are really excited about them.”

The vaccine is an individualised neoantigen therapy. It is designed to trigger the immune system so it can fight back against a patient’s specific type of cancer and tumour.

Known as mRNA-4157 (V940), the vaccine targets tumour neoantigens, which are expressed by tumours in a particular patient. These are markers on the tumour that can potentially be recognised by the immune system.

The jab carries coding for up to 34 neoantigens and activates an anti-tumour immune response based on the unique mutations in a patient’s cancer.

To personalise it, a sample of tumour is removed during the patient’s surgery, followed by DNA sequencing and the use of artificial intelligence. The result is a custom-built anti-cancer jab that is specific to the patient’s tumour.

“This is very much an individualised therapy and it’s far cleverer in some senses than a vaccine,” said Shaw. “It is absolutely custom-built for the patient – you couldn’t give this to the next patient in the line because you wouldn’t expect it to work.

“They may have some shared new antigens, but they’re likely to have their own very individual new antigens that are important to their tumour and so, therefore, it is truly personalised.”

The ultimate aim to permanently cure patients of their cancer, Shaw said. “I think there is a real hope that these will be the gamechangers in immunotherapy,” she said.

Phase 2 data found people with serious high-risk melanomas who had the jab alongside the immunotherapy Keytruda were almost half (49%) as likely to die or have their cancer come back after three years than those who were given only Keytruda.

Patients received 1mg of the mRNA vaccine every three weeks for a maximum of nine doses, and 200mg of Keytruda every three weeks (maximum 18 doses) for about a year.

The phase 3 global trial will now include a wider range of patients, and aims to recruit about 1,100 people. The UK arm aims to recruit at least 60 to 70 patients across eight centres, including in London, Manchester, Edinburgh and Leeds.

• Skin cancer
• Medical research
• Vaccines and immunisation
• UCL (University College London)

More on this story

UK scientists working on breast cancer monitor fitted in bra

Study offers hope in identifying high-risk prostate cancer patients

UK cancer study shows big fall in death rates since early 1990s

Sussex man doing well a year and a half after new brain cancer treatment

Cancer experts call on philanthropists to help fund ‘golden age’ of research

Princess of Wales’ diagnosis: cancers in young are rising, but so are survival rates

What is preventive chemotherapy and how effective is it? The Princess of Wales’ treatment explained

Drug that could slow womb cancer to be rolled out by NHS in England

UK trails other countries on waiting times for cancer treatment, study finds

Most viewed.