title: Emerging Molecular Biomarkers in Advanced Prostate Cancer: Translation to the Clinic.
abstract: 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.
authors.affiliation: 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.
authors.forename: Himisha
authors.initials: H
authors.lastname: Beltran
authors.affiliation: 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.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Antonarakis
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morris
authors.affiliation: 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.
authors.forename: Gerhardt
authors.initials: G
authors.lastname: Attard
mesh_terms: D004260:DNA Repair / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010793:Phthalazines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics*; D000071230:Transcriptional Regulator ERG / Q000235:genetics; D057170:Translational Research, Biomedical; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D010793:Phthalazines; D010879:Piperazines; D011944:Receptors, Androgen; C495901:TP53 protein, human; D000071230:Transcriptional Regulator ERG; D016159:Tumor Suppressor Protein p53; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C531550:olaparib