Interrogation of Aberrant DNA Repair in Sporadic Prostate Cancer
About Interrogation of Aberrant DNA Repair in Sporadic Prostate Cancer
What this means to patients:Understanding the extent and impact of alterations in DNA Damage Response pathways in prostate cancer patients will target specific DNA repair problems and allow effective Precision Medicine (tailored treatment regimens) based on molecular subtyping of patient DDR alterations matched to drug therapy.
Synopsis: DNA Damage Response (DDR) pathway alterations are changes in DNA repair mechanisms that promote genomic instability and have been associated with local and advanced prostate cancer. Dr. Knudsen and team will identify and comprehensively determine the frequency of abiraterone in DDR pathways at different stages of prostate cancer progression. They will determine the clinical relevance of these DNA repair defects in prostate cancer patients and their role in the development and progression of treatment-resistant prostate cancer. Previous studies showed that the DNA repair protein PARP1 is elevated in tumors of advanced prostate cancer patients. PARP1 is recruited to sites of androgen receptor function and is required for AR activity in both hormone-dependent and treatment refractory disease. PARP inhibition therefore has dual effects on cancerous cells; 1) impairs DNA repair in tumors and, 2) suppresses AR signaling—halting cancer progression. Dr. Knudsen and colleagues will evaluate effects of combination therapy with PARP inhibitors and next generation anti-androgens in treatment-resistant prostate cancer patients.
In addition, this team will determine the best positioning for PARP1-inhibitors in the clinical setting. Samples from prostate cancer patients undergoing clinical trials with PARP-inhibitors (NCI 9012 and TO-PARP trials) will be comprehensively examined for genomic biomarkers that indicate which patients will respond.These biomarkers will then be validated and developed into clinical-grade assays that will allow physicians to assign patients to receive these promising therapies.
Karen Knudsen, PhD
Thomas Jefferson University
Johann De Bono, MD, PhD, Royal Marsden Hospital; Felix Feng, MD, University of Michigan; Mark Rubin, MD, Weill Cornell Medical College.