Abstract A34: Targeting Protein Phosphatase 2A in Combination with PARP inhibitors for the treatment of high-grade serous epithelial ovarian cancer

Abstract

Abstract Ovarian cancer (OvC) is the deadliest of all female gynecologic malignancies, ranking as the fifth cause of cancer-related deaths among women. High-grade serous epithelial ovarian cancer (HGSOC) accounts for almost 90% of all forms of OvC, remaining as the most lethal subtype of ovarian malignancies. HGSOC is usually diagnosed at a later stage at which the disease has already progressed into metastatic, having a 5-year survival rate of only 17%. Treatment of HGSOC relies on aggressive approaches including surgery and platinum-based chemotherapies, with the majority of cases requiring combination of both. The molecular mechanism driving ovarian tumorigenesis is not fully understood, and its investigation is essential to provide better and novel therapeutic options for the treatment and cure of this disease. Targeted therapies have been vastly explored in the cancer research field due to their promise in reducing side effects by specifically targeting oncogenic pathways predominantly deregulated in human malignancies. DNA damage and repair (DDR) pathway aberrations and genomic instability are two main hallmarks of OvC. Extensive efforts in targeting this pathway have been devoted to introduce new drugs in the clinic that can target the DDR and homologous recombination (HR) pathways as therapeutic means for treatment of HGSOC. The use of PARP inhibitors (PARPi) to achieve synthetic lethality in OvC has been shown to have great promise in efficiently reducing tumor burden by specifically targeting tumor cells for cell death. However, PARPi’s antitumoral efficacy alone is limited by the status of the BRCA1/2 genes, narrowing down the patient population that can benefit from such therapies. Eventually, patients treated with PARPi alone relapse and develop resistant OvC, for which treatment options available are extremely limited. Our preliminary data show that first-in-class small-molecule activators of PP2A (SMAPs) in combination with PARPi can effectively reduce tumor burden in PDX models, promoting a synergistic effect in platinum-sensitive and -resistant OvC tumors, despite the BRCA gene status. Protein Phosphatase 2A (PP2A) and Protein Phosphatase 1 (PP1) account for 90% of all serine/threonine phosphatase activity in the cell and act as two main tumor suppressors. These phosphatases tightly regulate signaling pathways involved with cell cycle, growth, migration, metabolism, survival and many oncogenic pathways by counteracting kinases. HGSOC tumors express inactivated PP2A due to PPP2RA1 heterozygous loss, although lacking mutations, making it an ideal target for reactivation in these cancers. Moreover, we have shown that reactivation of PP2A via SMAPs leads to potent inhibition of several key DDR proteins. We have found that SMAPs treatment in BRCA1/2 WT tumors confers a “BRCAness” phenotype, which sensitizes tumors to DNA repair inhibitors such as PARPi. In sum, SMAPs can allow us to expand the patient population that can benefit from PARPi therapies and possibly overcome drug resistance. Citation Format: Rita A. Avelar, Amy Armstrong, Goutham Narla, Analisa DiFeo. Targeting Protein Phosphatase 2A in Combination with PARP inhibitors for the treatment of high-grade serous epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A34.