Progress in Prostate Cancer Research: Promising New Treatment Targets

The American Association for Cancer Research Annual Meeting 2022 was held in New Orleans in April. Presentations covered topics from cancer prevention to basic biology to clinical studies to survivorship. This month, we highlight discoveries from the cancer biology lab: two new potential targets for prostate cancer therapy.

A New Approach to Targeting the Androgen Receptor in Advanced Prostate Cancer

The androgen receptor (AR) is the main driver of prostate cancer and the primary therapeutic target. Medications include standard hormone therapy and the newer agents abiraterone, apalutamide, darolutamide, and enzalutamide. However, tumors frequently develop resistance to AR-targeted therapy and progress. Novel strategies to target AR are needed.

PCF-funded investigator Luke Gilbert, PhD (UCSF) and colleagues conducted a study to identify new regulators of AR, which have potential as treatment targets for prostate cancer. The team used the gene technology called CRISPR (clustered regularly interspaced short palindromic repeats) to look for molecules that influence prostate cancer’s growth.

By screening thousands of genes, the team identified several known and new AR regulators as potentially important. A molecule called PTGES3 was a top hit, with a previously unknown role in prostate cancer. After performing additional studies of PTGES3, to investigate its potential as a drug target, the team developed a series of small molecules that inhibit PTGES3 activity in cells. PTGES3 inhibitors blocked growth of AR-positive (but not AR-negative) prostate cancer cells, suggesting that this approach may be effective.

In ongoing studies, the team is further optimizing the chemistry and pharmacology of PTGES3 inhibitors, in order to develop a clinic-ready PTGES3 inhibitor that can be tested in clinical trials.

Take-home point: Researchers have used the gene-editing technology CRISPR to identify a potential new treatment target for prostate cancer called PTGES3.

“Internal Clock” Gene as a Potential Target for Prostate Cancer Therapy

Your body has a cyclical internal “circadian clock” that regulates functions, such as sleep and metabolism, as part of a daily rhythm. Disruptions to circadian rhythms have been linked to increased risk of prostate and other cancers. The “clock” also operates at a cellular level through certain circadian genes and proteins.

PCF Young Investigator Ayesha Shafi, PhD (Center for Prostate Disease Research, Uniformed Services University of the Health Sciences/The Henry M. Jackson Foundation for the Advancement of Military Medicine) has identified that the circadian gene CRY1 also functions in prostate cancer. It is associated with poor outcomes in patients with prostate cancer.

Dr. Shafi and team have shown that CRY1 is regulated by the androgen receptor, and that CRY1, in turn, regulates DNA damage repair and cell division. These studies identified CRY1 as a prostate cancer driver and as a potential new therapeutic target. Dr. Shafi continues to investigate how CRY1 regulates DNA repair and prostate cancer growth, and is exploring how it may be used in future treatments for prostate cancer.

Take-home point: CRY1 is a biological “clock” gene involved in repairing damaged DNA in prostate cancer, and may be a target for new treatments for the disease.

Progress in Prostate Cancer Research provides hope for finding a cure and the discovery of new treatments to minimize the impact of a man’s prostate cancer and maximize his quality of life. This regular ZEROHour supplement includes some of the latest research from the Prostate Cancer Foundation.