Mechanistic Insights on Localized to Metastatic Prostate Cancer Transition and Therapeutic Opportunities

Abstract

Prostate cancer is the most common non-cutaneous cancer among American men. Multiple mechanisms are involved in tumorigenesis and progression to metastases. While androgen deprivation therapy remains the cornerstone of treatment, progression to castration-resistant disease becomes inevitable. Aberrant pathway activations of PI3K/AKT due to PTEN loss, epithelial–mesenchymal transition pathways, homologous recombination repair, and DNA repair pathway mechanisms of resistance and cross-talk lead to opportunities for therapeutic targeting in metastatic castration-resistant prostate cancer. This review focuses on mechanisms of progression and key trials that evaluate the drugs and combinations that exploit these pathways.

Keywords:

• prostate cancer
• metastasis
• castration-resistant prostate cancer
• epithelial mesenchymal transition
• androgen receptor pathway inhibitors
• poly-ADP ribose pathway inhibitors

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Dr Jeanny Aragon-Ching has served as a member of Advisory Board/speaker’s Bureau for Pfizer, EMD Serono, Astellas/Seagen, BMS, Exelixis, AZD, and AVEO, during the conduct of the study. The other authors report no conflicts of interest in this work.

Additional information

Funding

Acknowledgement using the David Wohlscheid Fund.