Precision Targets for Intercepting the Lethal Progression of Prostate Cancer: Potential Avenues for Personalized Therapy

SIMPLE SUMMARY: Metastatic prostate cancer is incurable and lethal. Tumor growth is initially reduced by radiation, surgery, or hormone therapy and later, by pairing them with chemotherapy for advanced cancer. Recent innovations have helped to develop prescription drugs against certain prostate cancer types, showing gene alterations that prevent the repair of damaged DNA or activate the body’s anti-cancer natural immune defense. A panel of genes has been identified whose cancer genome alterations may predict whether non-metastatic prostate cancer would go on to metastasize. The activity of these genes may help to guide treatment decision for non-metastatic cancer with the choice for non-aggressive versus debilitating aggressive options. The probing of prostate cancer genome has uncovered hormonal abnormalities and genome changes specific to individual patients and studies are revealing how these changes can lead to treatment failure. The discovery of new druggable vulnerabilities of the cancer cells has presented opportunities to develop precision treatments of metastatic prostate cancer tailored to individual patients. ABSTRACT: Organ-confined prostate cancer of low-grade histopathology is managed with radiation, surgery, active surveillance, or watchful waiting and exhibits a 5-year overall survival (OS) of 95%, while metastatic prostate cancer (PCa) is incurable, holding a 5-year OS of 30%. Treatment options for advanced PCa—metastatic and non-metastatic—include hormone therapy that inactivates androgen receptor (AR) signaling, chemotherapy and genome-targeted therapy entailing synthetic lethality of tumor cells exhibiting aberrant DNA damage response, and immune checkpoint inhibition (ICI), which suppresses tumors with genomic microsatellite instability and/or deficient mismatch repair. Cancer genome sequencing uncovered novel somatic and germline mutations, while mechanistic studies are revealing their pathological consequences. A microRNA has shown biomarker potential for stratifying patients who may benefit from angiogenesis inhibition prior to ICI. A 22-gene expression signature may select high-risk localized PCa, which would not additionally benefit from post-radiation hormone therapy. We present an up-to-date review of the molecular and therapeutic aspects of PCa, highlight genomic alterations leading to AR upregulation and discuss AR-degrading molecules as promising anti-AR therapeutics. New biomarkers and druggable targets are shaping innovative intervention strategies against high-risk localized and metastatic PCa, including AR-independent small cell-neuroendocrine carcinoma, while presenting individualized treatment opportunities through improved design and precision targeting.