Novel Synergistic ATR Inhibitor Combinations for Ovarian Cancer Therapy
Abstract
Large scale genomic studies have demonstrated that high grade serous ovarian cancers (HGSOCs) exhibit increased replication stress due to near universal loss of the G1/S checkpoint, premature S phase entry, oncogenic driver activation and deficiency in homologous recombination repair. In this application we address the potential of targeting the replication stress (RS) and the replication stress response (which is facilitated by the ATR kinase) in ovarian cancer and have proposed a set of experiments to facilitate preclinical development of novel synergistic ATRi combinations in this disease. In the Aims 1 and 2 of this award we have proposed to perform in vitro and in vivo studies to evaluate the therapeutic efficacy of ATRi in combination with CDK5, PI3K and EZH2 inhibitors in HGSOC lines, organoid models and PDX models. In Aim 3, we have proposed to evaluate the therapeutic efficacy of ATRi in combination with immune checkpoint inhibitors in genetically engineered mouse models (GEMMs) and in Aim 4 we propose to define and validate a RS biomarker of response to ATRi in tumors from patients with platinum resistant HGSOC treated on a randomized trial of gemcitabine vs. gemcitabine combined with ATRi berzosertib. In the first year of the award, we have been doing preclinical work on combinations of ATRi with PI3Ki and CDK5i inhibitors as well as anti-PD-1 antibodies and we have been able to define a biomarker of replication stress that correlates response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2022
- Accession Number
- AD1198613
Entities
People
- Panagiotis A Konstantinopoulos
Organizations
- Dana–Farber Cancer Institute