Predicting Sensitivity to DNA Repair Inhibition in Short-Term Patient-Derived Ovarian Cancer Organoids Beyond PARP Progression
Abstract
Rationale and Objective: High-grade serous cancer (HGSC) is the most common type of ovarian cancer. Seventy percent of ovarian cancers present with advanced stage and metastatic disease, and less than half of ovarian cancer patients are alive 5 years after diagnosis. One in three women with ovarian cancer have tumors that are unable to repair a certain type of DNA damage by having either a genetic hereditary mutation or a mutation in the tumor tissue of BRCA1 or 2. Besides BRCA mutations, there are additional genes that affect DNA damage repair. Those with tumors that lack this crucial DNA repair ability are also called homologous recombination deficient (HRD). Presence of BRCA mutation or HRD can be determined by assays or genomic tests and are considered biomarkers. PARP inhibitors (PARPi) are oral medications that inhibit the PARP protein in cells. They stop the ability for a cell to repair single-stranded breaks. Presence of single-stranded breaks leads to double-stranded breaks, which are lethal for the cell unless it is repaired by BRCA1 or 2 or by mechanism of the HRD pathway. Therefore, in ovarian cancer, those with BRCA mutation or HRD particularly benefit from PARPi to specifically target and destroy cancer cells. PARPi have been widely tested in patients with ovarian cancer, demonstrating the greatest benefit for survival in patients with BRCA1/2 mutation or those who are HRD. A recent large clinical trial demonstrated benefit of PARPi for those BRCA mutated or HRD, but also a subset of patients who did not have HRD or homologous recombination proficient (HRp) had a shorter, but statistically significant benefit from PARP inhibitors. The trial, however, was not designed to examine whether those who are HRp have benefit with PARPi, and therefore use of PARPi in this specific subset of patients is still debated. Nonetheless, the Food and Drug Administration (FDA) has granted approval for use of PARPi for ovarian cancer patients with BRCA mutation or who are HRD for maintenance therapy in the front line setting after chemotherapy, for those with recurrent ovarian cancer who recur > 6 months after platinum-based chemotherapy, and also most recently in April 2020, for those with ovarian cancer regardless of BRCA or HRD status after frontline chemotherapy. The recent explosion in clinical trials with PARPi has revolutionized the treatment landscape for patients with ovarian cancer and have demonstrated increased survival with durable responses, which is remarkable for these patients, who typically present at late stage and traditionally have dismal prognosis. Overall, this means that the vast majority of ovarian cancer patients will have PARPi as a treatment at some point in their disease journey. The majority of patients on PARPi, however, will eventually become resistant to this therapy, resulting in a population that requires new treatment options to overcome resistance. Currently, the efficacy of re-challenging HGSC patients with PARPi at the time of disease progression is an area of high-priority clinical research. Preclinical studies have shown that combining agents that target key components of the DNA damage repair pathway have overcome resistance acquired after use of PARPi. However, the drug resistance mechanisms are very heterogeneous and there are multiple pathways. Generating a method to quickly test and identify drug combinations to see whether the tumor tissue would have a response would be an efficient way of determining what combinations work best and in which clinical scenarios. Our team has the expertise and capability of forming 3D tumor organoid models from patient ovarian cancer tumor tissue. The organoids have the same characteristics of the tumors from which the tissue has been biopsied. By forming these organoids, it allows a mechanism to rapidly test drug combinations on tissue and to evaluate whether the tumor tissue will respond to those drug combinations afte
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110407
Entities
People
- Lilian Gien
Organizations
- Sunnybrook Research Institute
- United States Army