Emerging Molecular Biomarkers in Advanced Prostate Cancer: Translation to the Clinic

Recent clinical and preclinical studies focused on understanding the molecular landscape of castration-resistant prostate cancer (CRPC) have provided insights into mechanisms of treatment resistance, disease heterogeneity, and potential therapeutic targets. This work has served as a framework for several ongoing clinical studies focused on bringing novel observations into the clinic in the form of tissue, liquid, and imaging biomarkers. Resistance in CRPC typically is driven through reactivation of androgen receptor (AR) signaling, which can occur through AR-activating point mutations, amplification, splice variants (such as AR-V7), or other bypass mechanisms. Detection of AR aberrations in the circulation negatively impacts response to subsequent AR-directed therapies such as abiraterone and enzalutamide. Other potentially clinically relevant alterations in CRPC include defects in DNA damage repair (at either the somatic or germline level) in up to 20% of patients (with implications for PARP1 inhibitor therapy), PI3K/PTEN/Akt pathway activation, WNT signaling pathway alterations, cell cycle gene alterations, and less common but potentially targetable alterations involving RAF and FGFR2. Imaging biomarkers that include those focused on incorporating overexpressed androgen-regulated genes/proteins, such as prostate-specific membrane antigen (PSMA) and dihydrotestosterone (DHT) in combination with CT, can noninvasively identify patterns of AR-driven distribution of CRPC tumor cells, monitor early metastatic lesions, and potentially capture heterogeneity of response to AR-directed therapies and other therapeutics. This article focuses on the current state of clinical biomarker development and future directions for how they might be implemented into the clinic in the near term to improve risk stratification and treatment selection for patients.

American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting. 2016 [Epub]

Himisha Beltran, Emmanuel S Antonarakis, Michael J Morris, Gerhardt Attard

From Weill Cornell Medicine, New York, NY, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, New York, NY; The Institute of Cancer Research, London, United Kingdom, The Royal Marsden Hospital, London, United Kingdom., From Weill Cornell Medicine, New York, NY, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, New York, NY; The Institute of Cancer Research, London, United Kingdom, The Royal Marsden Hospital, London, United Kingdom., From Weill Cornell Medicine, New York, NY, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, New York, NY; The Institute of Cancer Research, London, United Kingdom, The Royal Marsden Hospital, London, United Kingdom., From Weill Cornell Medicine, New York, NY, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, New York, NY; The Institute of Cancer Research, London, United Kingdom, The Royal Marsden Hospital, London, United Kingdom.

E-Newsletters

Newsletter subscription

Free Daily and Weekly newsletters offered by content of interest

The fields of GU Oncology and Urology are rapidly advancing. Sign up today for articles, videos, conference highlights and abstracts from peer-review publications by disease and condition delivered to your inbox and read on the go.

Subscribe