Exploiting DNA Repair Vulnerabilities as a Precision Oncology Target in Metastatic Prostate Cancer

About Exploiting DNA Repair Vulnerabilities as a Precision Oncology Target in Metastatic Prostate Cancer
  • Inherited alterations in DNA-damage repair genes occur in ~8-10% of metastatic castrate resistant prostate cancer (mCRPC) patients, while another ~10-20% of mCRPC patients have tumors with acquired DNA-damage repair gene alterations. Alterations in these genes promote the development of aggressive prostate cancer but also serendipitously confer sensitivity to treatment with PARP-inhibitors and/or platinum chemotherapy (carboplatin).
  • Dr. Nelson and team are identifying and characterizing DNA-damage repair gene alterations that occur in tumors from mCRPC patients.
  • The genomes of mCPRC patients will be sequenced to identify inherited alterations in DNA-damage genes that promote prostate cancer and the frequency at which they occur.
  • A Phase II clinical trial will be initiated to test the efficacy of docetaxel plus carboplatin in mCRPC patients harboring tumors with inherited or acquired biallelic inactivation of DNA repair genes.
  • Inherited or tumor-acquired alterations identified in DNA repair genes with a previously unknown significance will be tested for sensitivity to PARP-inhibitors and platinum chemotherapy in laboratory models.
  • Prostate cancer laboratory models that have been genetically engineered not to express the DNA-damage repair genes BRCA1, BRCA2 and ATM will be studied for sensitivity to carboplatin versus two different PARP inhibitors to guide the treatment of patients with similar alterations.
  • Finally, methods will be developed to acquire and sequence the genomes of circulating tumor cells obtained from patient blood to create minimally invasive biomarker tests that can identify patients who have alterations in DNA damage repair pathways and should be considered for treatment with PARP inhibitors or platinum chemotherapy.

What this means for patients: Precision medicine approaches for the treatment of prostate cancer patients require the identification of genomic alterations that confer sensitivity to specific treatments. Dr. Nelson and team are identifying and characterizing DNA-damage repair gene alterations that occur in ~20-30% of prostate tumors. If successful, this study will result in the development of biomarker tests that identify patients who should be treated with PARP inhibitors or platinum chemotherapy, and will enable population-based screening to identify individuals at increased risk for prostate cancer.

Principal Investigator:

Peter Nelson, MD (University of Washington), Phillip Kantoff, MD (Harvard: Dana Farber Cancer Institute) & Bruce Montgomery, PhD (University of Washington)

Co-investigators:

Heather Cheng, MD, PhD (University of Washington), Mary-Claire King, PhD (University of Washington), Eliezer Van Allen, MD, PhD (Harvard: Dana Farber Cancer Institute), Ruth Etzioni, PhD (Fred Hutchinson Cancer Research Center), Colin Pritchard, MD, PhD (University of Washington)