Treatment of Homologous Recombination-Proficient Ovarian Cancer and PARP Inhibitor-Resistant Tumors Using PP2A Reactivation Strategies
Abstract
Ovarian cancer is the leading cause of cancer death in women. High-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of all female gynecological malignancies. Current HGSOC treatments include aggressive surgical and platinum-based chemotherapy approaches. Many patient respond well to this first-line of treatment; however, up to 75% of patients have tumor recurrence. Therefore, there is an urgent need for the development of novel and more efficient therapies for the treatment of this disease to prevent the tumors from coming back or treating recurrent tumors. Therapies that target a specific gene in a tumor have shown great promise in cancer due to their specificity; however, effective targets to treat HGSOC are lacking due to the variety and complexity of molecules and pathways involved. Ideally, a regulatory molecule that is commonly lost in HGSOC and can act on multiple proteins associated with tumor recurrence will be the ideal target for the development of therapeutics to treat patients. Our laboratory recently found that the tumor suppressor Protein Phosphatase 2A (PP2A) is lost in >90% of HGSOC tumors second only to p53, which is the most common gene altered in HGSOC. PP2A is a protein that accounts for the majority of cellular Serine/Threonine phosphatase activity in a tumor cell therefore simultaneously regulates multiple proteins in a cell. Remarkably, we have found that a novel drug that reactivates PP2A, which are called Small Molecule Activators of PP2A (SMAPs), can effectively kill a panel of HGSOC cells that are derived from patient tumors as well as decrease tumor growth in vivo in numerous genetically distinct HGSOC patient-derived mouse models. SMAPs are orally bioavailable, non-toxic and were discovered through the reverse engineering of the tricyclic neuroleptics that have been FDA-approved for many years. We found that the way these drugs work is through degradation of numerous proteins that control a cell’s response to DNA damage and, when combined with another drug that works in a similar fashion (PARP inhibitors), you get a more pronounced effect on cell death. Most importantly, we found that SMAPs can allow expansion of the patient population that can benefit from PARPi therapies and possibly overcome drug resistance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210270
Entities
People
- Analisa DiFeo
Organizations
- United States Army
- University of Michigan