Emerging Therapeutic Approaches for Prostate Cancer

Approximately 1 in 8 men will be diagnosed with prostate cancer, a disease which accounts for the second highest number of male, cancer-related deaths in the United States.^1,2 Early-stage prostate cancer growth is usually androgen-dependent and therefore responds well to hormone therapy. So why do so many men lose their battle? Many late-stage cancers like castration resistant prostate cancers (CRPCs) are androgen-independent and no longer responsive to hormone therapy. Thus, early detection is a life-saver. Simple blood tests monitoring prostate-specific antigen (PSA) are routinely performed to screen for men who require further testing to confirm diagnosis.

Currently, the first line of defense to CRPC is abiraterone, an androgen biosynthesis inhibitor that prevents the production of androgen receptor (AR) in the testes. Enzalutamide, an AR antagonist, is also commonly used for CRPCs; however, the cancer cells will eventually become resistant. Therefore, developing new therapies or combination therapies is a must to effectively help patients with late-stage prostate cancers. Several gene mutations identified in prostate cancers have been identified as possible therapeutic targets, including the TMPRSS2-ERG fusion protein present in 50% of prostate cancers. Other gene mutations frequently observed in include ERG, TMPRSS2, CHD1, FOXA1, SPOP, and BRCA1/2.  Additionally, AR variants, like AR-V7 and AR-V567, also continue to attract much interest. These variants tend to arise through aberrant splicing and lack a ligand-binding domain, which contributes to androgen-independent growth in prostate cancer cells. This gives the tumor cells the ability for sustained proliferation, one of the hallmarks of cancer. AR-V7 is one of the main drivers of CRPC and is highly expressed in metastatic and CRPC. Thus, therapeutics aimed at controlling the splicing events that cause different variants to arise are being explored as well as therapeutics that target a specific variant.^3,4

Another combinatory approach is to target epigenetic machinery along with immunotherapies to address the tumor’s ability to avoid immune destruction, another cancer hallmark.⁵ Treating patients with an immunotherapy alone is usually not a favorable treatment approach since prostate cancers tend to lack T cell infiltration and are therefore considered to be immunologically “cold”. EZH2 is a methyltransferase enzyme that regulates chromatin to silence gene function. It is highly expressed in CRPCs and EZH2 inhibitors have shown promise in CRPCs and neuroendocrine prostate cancers that subsequently develop with enzalutamide treatment. EZH2 inhibitors have also been shown to flip the “cold” switch in prostate cancers by reactivating the STING pathway, making them more responsive to immunotherapies.

PARP inhibitors such as olaparib and rucaparib may play a role in personalized medicine for patients with CRPC or for the 30% of patients with a mutation in the homologous recombination repair pathway. However, the overall efficacy of a general PARP inhibition remains to be determined.^6,7

Taxanes, which are a standard chemotherapy, can be used in combination with androgen signaling inhibitors like abiraterone or enzalutamide. In one study, treating patients with cabazitaxel with the androgen signaling inhibitors in patients previously treated with docetaxel and AR inhibitors improved clinical outcomes.^8,9

Promising therapeutic approaches earlier in the discovery stage include the degradation of a component of SWI/SNF, a chromatin remodeling complex that promotes access of transcription factors to enhancer elements that increases expression of FOXA1 and ERG. Researchers have also developed a drug, currently entering Phase 1A clinical trials, that restores a long noncoding RNA that suppresses androgen receptor expression. Finally, scientists are attacking the mechanisms that confer resistance to AR inhibitor therapies. Prostate cancer cells have increased expression of glucocorticoid receptor, which share similarities with the androgen receptor, to compensate when AR signaling is inhibited¹⁰. When the glucocorticoid receptor is inhibited, tumors regain their responsiveness to first line treatment options.

The prognosis for castration resistant prostate cancer is not encouraging; however, novel combination therapies are constantly being evaluated to improve patient outcomes. Research to discover effective combination therapies will only give clinicians a larger arsenal to use when fighting castration resistant prostate cancer, ultimately saving lives.

Select References

1. American Cancer Society – Key Statistics for Prostate Cancer. https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html
2. National Cancer Institute – Prostate Cancer. https://www.cancer.gov/types/prostate
3. Liu LL, Xie N, Sun S, Plymate S, et al. Mechanisms of the androgen receptor splicing in prostate cancer cells. 2014;33(24):3140-50. doi: 10.1038/onc.2013.284
4. Paschalis A, Sharp A, Welti JC, et al. Alternative splicing in prostate cancer. Nat Rev Clin Oncol. 2018;15(11):663-675. doi: 10.1038/s41571-018-0085-0.
5. Morel KL, Sheahan AV, Burkhart DL, et al. EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer. Nat Cancer. 2021;2(4):444-456. doi: 10.1038/s43018-021-00185-w.
6. McFarland TR, Kessel A, Swami U, Agarwal N. Development of PARP inhibitor combinations for castration resistant prostate cancer unselected for homologous recombination repair mutations. Am J Transl Res. 2021;13(7):7427-7439.
7. Antonarakis ES, Gomella LG, Petrylak DP. When and How to Use PARP Inhibitors in Prostate Cancer: A Systematic Review of the Literature with an Update on On-Going Trials. Eur Urol Oncol. 2020;3(5):594-611. doi: 10.1016/j.euo.2020.07.005.
8. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019;381(26):2506-2518. doi: 10.1056/NEJMoa1911206.
9. Zhang PF, Xie D, Li Q. Cost-effectiveness analysis of cabazitaxel for metastatic castration resistant prostate cancer after docetaxel and androgen-signaling-targeted inhibitor resistance. BMC Cancer. 2021;21(1):35. doi: 10.1186/s12885-020-07754-9.
10. Shah N, Wang P, Wongvipat J, Karthaus WR, Abida W, Armenia J, Rockowitz S, Drier Y, Bernstein BE, Long HW, Freedman ML, Arora VK, Zheng D, Sawyers CL. Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. Elife. 2017 Sep 11;6:e27861. doi: 10.7554/eLife.27861.