CLEVELAND, OH — Two studies conducted by the Cleveland Clinic revealed how a testosterone-related genetic abnormality can help predict individual patient responses to specific prostate cancer therapies. The studies, published in the October 12 issue of JAMA Oncology, suggest that men who inherit this variant would benefit from a personalized treatment plan that targets specific hormonal pathways.
In the first study, Nima Sharifi, M.D., of the Cleveland Clinic Lerner Research Institute, and his team studied the role of the gene variant known to science as “HSD3B1(1245C)” in two different prostate cancer patient populations, after those patients received androgen deprivation therapy (ADT). ADT works by blocking prostate cancer’s supply of male hormones in the testes, and is the go-to treatment for the recurrent form of the disease. However, ADT is notorious for suddenly losing its effectiveness. This allows the cancer to grow and metastasize.
Dr. Sharifi discovered that prostate cancer cells with the HSD3B1(1245C) abnormality survive ADT by producing their own androgens.
In the first study, 213 prostate cancer patients whose tumor recurred after radiation treatment were then treated with ADT. Dr. Sharifi found that patients with the HSD3B variant developed metastatic cancer and it developed more rapidly than those without the variant. He and his team showed that the genetic variant was predictive of the time to develop metastasis.
The second study examined a group of 90 men with metastatic prostate cancer that had become resistant to ADT. These patients were subsequently treated with the drug ketoconazole, which blocks the production of androgens outside of the testes, such as those developed by prostate cancer cells evading treatment.
Surprisingly, men with the genetic anomaly fared better on ketoconazole than men without the variant. This finding raises the possibility that targeting the variant tumors’ backup androgen supply could be a successful strategy when ADT fails.
“We hypothesized that HSD3B1(1245C) variant tumors become resistant to ADT because they have a backup supply of androgens,” said Dr. Sharifi. “However, relying on these extra-gonadal androgens makesthem more sensitive to ketoconazole.”
Unfortunately, with the current state of prostate cancer treatments as they are, the outlook of men with this particular gene variant remains poor; in 2017, Sharifi received a Top Ten Clinical Research Achievement award from the Clinical Research Forum for his landmark discovery that men who carry the HSD3B1(1245C) variant are more likely to die from their disease. However, his most recent studies in the identification of HSD3B1(1245C) in patients sets up the gene as a predictive biomarker to help in the diagnosis and treatment of their prostate cancer. It also helps with the ongoing research and development of next-generation androgen inhibitors, such as abiraterone and enzalutamide.
These discoveries are part of an existing trend in medical science to individualize the treatment of a cancer patient, treating each body as a unique environment and where cancer treatment is no longer considered a formulaic, one-size-fits-all formula.
“We are hopeful that these findings will lead to more personalized and effective treatments for prostate cancer,” said Dr. Sharifi. He continues, “If men carry a specific testosterone-related genetic abnormality, we may be able to personalize their therapy and treat specific patients more aggressively.”
In addition, National Foundation for Cancer Research (NFCR) sponsored scientist Dr. Paul B. Fisher at Virginia Commonwealth University and his team are developing new viral-based treatments for patients with metastatic prostate cancer that are unresponsive to ADT and other treatments and who have no other choices. The gene therapy involves an immune system cytokine, either Interferon gamma (IFNγ) or MDA-7/IL- 24 — the latter discovered by Dr. Fisher and works by inducing metastatic cells to commit cell suicide (apoptosis). Prostate cancer spreads to bone in 73% of patients with metastatic prostate cancer and MDA-7/IL- 24 also has anti-bone metastatic properties. MDA-7/IL- 24 has been shown to be safe from results in a Phase I clinical trial which should allow this potential new treatment for advanced prostate cancer to enter clinical trials easily upon completion of this pre-clinical research.