DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Mutator Phenotypes that Better Predict PARP Inhibitor Response in Ovarian Carcinomas

Principal Investigator: SWISHER, ELIZABETH
Institution Receiving Award: WASHINGTON, UNIVERSITY OF
Program: OCRP
Proposal Number: OC160274
Award Number: W81XWH-17-1-0070
Funding Mechanism: Clinical Development Award
Partnering Awards:
Award Amount: $928,968.00
Period of Performance: 8/1/2017 - 7/31/2021


PUBLIC ABSTRACT

Most women with ovarian cancer require chemotherapy for treatment. When cells are growing and dividing, they have important processes to fix mistakes in DNA that would otherwise accumulate. DNA repair is a critical and universal cell function. Many ovarian cancers have specific defects in DNA repair that make them sensitive to a new class of drugs called PARP inhibitors. PARP inhibitors are particularly effective against cancers that have alterations in the BRCA1 or BRCA2 genes. These are genes in which inherited mutations increase the chance of getting breast and ovarian cancers. BRCA1 and BRCA2 function in DNA repair, and cancers associated with BRCA1 or BRCA2 mutations are deficient in a certain type of DNA repair called homologous recombination. When homologous recombination does not work right, cancer cells rely on other types of DNA repair that result in more errors in replicating DNA. These errors can lead to characteristic patterns of DNA alterations in the cancer cell. If we sequence all the DNA in a cancer (called whole genome sequencing), we can detect patterns of alterations in the DNA that are characteristic of homologous recombination deficiency. We propose to perform whole genome sequencing on cancers from 120 women who participated in ARIEL2, a PARP inhibitor clinical trial for recurrent ovarian cancer. We believe we will be able to predict who will respond to a PARP inhibitor by evaluating specific patterns of DNA alterations. Tumor tissue was already collected just before treatment from women in ARIEL2, and we already know who responded well or failed to respond to the treatment. Therefore, the cancer samples from ARIEL2 patients are a perfect opportunity to test our prediction. We will use the information that we acquire to develop a new clinical test based on patterns of DNA alterations to better predict which women with ovarian cancer should be treated with a PARP inhibitor. In this manner, we can identify women with ovarian cancer who do not have BRCA1 or BRCA2 mutations, but who also have a good chance of responding to PARP inhibitors.