Abstract 3857: Pharmacological reactivation of the tumor suppressor protein phosphatase 2A as a novel approach for the treatment of breast cancer
Authors: Farrington Caroline C. , Wang Xiaoyan , Janghorban Mahnaz , Liang Juan , Difeo Analisa , Sears Rosalie , Narla Goutham 
Published: July 2016

Abstract
PP2A is a phosphatase that is functionally dysregulated and inactivated in over 50% of all breast cancers independent of histological type. While much attention has focused on oncogenic kinases as targets for cancer treatment, therapeutic targeting of phosphatases, the key negative regulators of these same signaling pathways, has remained largely unexplored. Starting with the observation that tricyclic neuroleptic drugs exert anticancer effects, our laboratory reverse engineered these drugs to generate a novel series of compounds that retain the anti-proliferative effects and favorable pharmacokinetic properties but are devoid of the undesirable central nervous system pharmacology of the parent drugs. It was subsequently demonstrated that these first generation novel derivatives exert anticancer effects in cell culture and xenograft models of cancer (without overt toxicity) by modulation of critical oncogenic signaling pathways. Recently, it was determined that the molecular basis of the actions of these novel derivatives is the activation of PP2A. Comprehensive profiling for activity in a panel of 240 cancer cell lines has shown that these first-in-class small molecule activators of PP2A (SMAPs) have significant anti-proliferative activity in breast cancer cell lines, and studies have been extended to disease relevant in vivo models (patient derived xenograft, GEMM, and traditional xenograft models). PP2A's ability to negatively regulate a diverse set of oncogenic drivers in breast cancer means SMAPs are able to exert their effects through multiple biological mechanisms, swiftly disrupting cellular energetics and metabolism, inducing apoptosis and inhibiting proliferation. This will be exhibited through a variety of biological assays evaluating cell growth, apoptosis and changes in cellular metabolism. Target engagement assessed via western blotting demonstrates inhibition of PP2A targets critical for mediating SMAP activity, notably c-MYC and AKT. As a result, this research demonstrates SMAPs have potent activity in a wide variety of breast cancer contexts where response to current therapies is modest and limited by the development of treatment resistance. Thus, SMAPs may be a viable treatment option for high-risk populations of patients who do not respond to the current standard of care. This research strives to demonstrate that therapeutic reactivation of PP2A may represent a novel approach for breast cancer treatment and that these molecules may favorably impact the lives of women suffering from breast cancer.
Citation Format: Caroline C. Farrington, Xiaoyan Wang, Mahnaz Janghorban, Juan Liang, Analisa Difeo, Rosalie Sears, Goutham Narla. Pharmacological reactivation of the tumor suppressor protein phosphatase 2A as a novel approach for the treatment of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3857.