Abstract 2074: Bioactive marine drugs target acquired oncogenic burden in resilient pancreatic cancer

Abstract

Abstract The upsurge of marine-derived therapeutics for cancer treatment is evident, with many drugs in clinical use and in clinical trials. Seaweeds harbor large amounts of polyphenols and their anti-cancer benefit is linear to their anti-oxidant activity. Our studies identified three superlative anti-cancer seaweed polyphenol drug candidates (SW-PD). We investigated the acquisition of oncogenic burden in radiotherapy-resilient pancreatic cancer (PC) that could drive tumor relapse, and elucidated the efficacy of SW-PD candidates as adjuvants in genetically diverse in vitro systems (Panc-1, Panc-3.27, BxPC-3, MiaPaCa-2) and a mouse model of radiation-residual disease. For residual PC studies, PC xenografts developed in nude mice were selectively exposed to clinically relevant fractionated irradiation, (2 Gy/day for 5 days per week for a total of 3 weeks), to a total dose of 30 Gy. QPCR profiling of custom archived 88 oncogenes in therapy-resilient PC cells identified a ‘shared’ activation of 40 oncogenes. SW-PD pre-treatment inflicted a significant mitigation of acquired (shared) oncogenic burden, in addition to drug- and cell-line-specific repression signatures. Tissue-microarray with IHC of radiation-residual tumors in mice signified acquired cellular localization of key oncoproteins (Fosb, cFos, Fra2, cMYC, MYB, NF2) and other critical architects (SELE, CD73, Cytokeratins, Col3, Decorin, and Sulf2). Conversely, SW-PD treatment inhibited the acquisition of these critical drivers of tumor genesis, dissemination, and evolution. Heightened death of resilient PC cells with SW-PD treatment validated the translation aspects. The results defined the acquisition of oncogenic burden in resilient PC and demonstrated that the marine polyphenols effectively target the acquired oncogenic burden and could serve as adjuvant(s) for PC treatment. Citation Format: Sheeja Aravindan, Somasundaram T. Somasundaram, Mohan Natarajan, Terence S. Herman, Natarajan Aravindan. Bioactive marine drugs target acquired oncogenic burden in resilient pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2074.