Novel Synergistic ATR Inhibitor Combinations for Ovarian Cancer Therapy
Abstract
DNA replication is the process by which a copy of the entire DNA is made in a cell before the cell divides. When DNA replication is slowed down or obstructed, cells experience “replication stress,” which, when severe, may result in significant DNA damage and cell death. To survive replication stress, cells depend on a specific protein called ATR, which is responsible for protecting them from the effects of replication stress by: (1) stopping the cell cycle, (2) activating repair of the DNA, and (3) stabilizing the replication forks, i.e., the areas where the DNA replication takes place. The critical role of ATR in protecting cells from replication stress is highlighted by the fact that, when ATR is inhibited (using specific drugs called ATR inhibitors) in cells with high replication stress, lethality is promptly induced. Several studies have shown that ovarian cancer cells (particularly high-grade serous ovarian cancer cells) exhibit very high replication stress due to many reasons, but primarily because they divide quickly. Given the prevalence of DNA replication stress in high grade serous ovarian cancers (HGSOCs), inhibition of ATR may be an effective strategy against these tumors. As proof of principle for the potential of ATR inhibition in HGSOC, we recently reported a randomized phase 2 (RP2) study in women with platinum-resistant HGSOC, which showed that addition of the ATR inhibitor (ATRi) berzosertib to gemcitabine improved outcome. Additionally, we and others have previously shown that targeting ATR may also be a promising strategy for patients with HGSOCs that have become PARP inhibitor (PARPi) resistant (i.e., patients with cancers for which PARPi have stopped working); this is because many mechanisms of PARPi resistance depend on activation of ATR. However, unlike gemcitabine, ATRi have been challenging to combine with other chemotherapy drugs due to overlapping toxicities (mainly reduced blood counts), which require significant reductions of the doses and/or use of abbreviated treatment schedules. Therefore, novel, non-chemotherapy-based, ATRi combinatorial strategies are needed. In our preliminary work, we used two high-throughput approaches (PRISM screening and CRISPR-based functional screens) to identify targets whose inhibition may enhance the activity of ATR inhibitors. Results of these screens identified that targeting CDK5, EZH2, and PI3K may enhance the activity of ATR inhibition, and we have already been unraveling the mechanisms underlying this synergism (enhanced activity). Furthermore, we and others have previously shown that inhibition of DNA Damage Response proteins such as PARP and ATR may enhance the activity of immunotherapy. Based on our preliminary data, we propose to develop novel ATR inhibitor combinatorial strategies that combine ATRi with: (1) targeted agents such as CDK5, EZH2, and PI3K inhibitors and (2) immunotherapy with PD-1/PD-L1 inhibitors. We propose to test these strategies in various preclinical models of HGSOC, including three-dimensional multicellular “organoid” cultures that mimic high-grade serous ovarian cancer and where functional studies on DNA repair and replication stress can be performed, as well as in patient-derived mouse models of ovarian cancer, whereby cells from patients with ovarian cancer have been injected and grown in mice. These models (including models that are resistant to PARP inhibitor therapy) are unique, because they closely resemble the primary ovarian cancer (where they came from) and therefore may offer powerful predictive information about the effectiveness of experimental drugs. To test immunotherapy combinations, we intend to use novel, genetically engineered mouse models of high-grade serous ovarian cancer that have an intact immune system and are therefore prime models to evaluate the potential synergism of ATR inhibition with immunotherapy. Finally, an important aim of our proposal is to identify predictive biomarkers of r
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110604
Entities
People
- Panagiotis A Konstantinopoulos
Organizations
- Dana–Farber Cancer Institute
- United States Army