Abstract B002: Modeling evolutionary therapy for GI malignancies

Abstract

Abstract Despite development of personalized treatments GI cancer like pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) remain dismal outcomes. While some patients are potentially curable with surgery and chemotherapy, most unresectable cases are invariably lethal. To advance patient care, we rely on clinical trials to test new therapeutic approaches. Here, we assume that the highest dose of a drug that does not cause severe toxicities is optimal for cancer treatment. However, this treatment strategy, in many cases, may be more harmful for the patient. Adopting principles from the field of evolutionary biology and pest management could offer more effective strategies that can be used for patients with metastatic PDAC and CRC. Resistance mechanisms are assumed to come with an energy cost, making the organism/cell less fit than others in the population. When high doses of treatment are applied, it results in a significant selection gradient by eliminating sensitive populations, freeing resources and facilitating resistant population growth. Such evolutionary dynamics and interactions within the tumor microenvironment can be modeled and exploited, in the form of adaptive strategies, for treatment of CRC and PDAC. It is our central hypothesis that integration of evolutionary dynamics and into PDAC and CRC treatment will delay emergence of resistance, enhance quality of life, and improve clinical outcomes. Our preliminary observations in co-cultured drug sensitive and resistant cell containing spheroids show that a higher proportion of drug sensitive cells inhibits the proliferation of drug resistant cells over time, in the presence of chemotherapeutic agents 5-FU and Oxaliplatin. We also demonstrate a role for the MLL family of histone methyltransferases in the epigenetic regulation of genes involved in chemoresistance. RNA-seq data has shown differential gene expression in metabolic genes regulated by histone methyltransferase KMT2A, KM2TB and KMT2D knockout (KO) cells including Gstt1, CYP26B1 and PYGL. In addition to this, KMT2A, KM2TB and KMT2D KOs show differential sensitivity to chemotherapeutic agents Gemcitabine, SN-38, 5-FU and Oxaliplatin. Further, analysis of KMT2A, KM2TB and KMT2D KO cells will provide mechanistic insight of the epigenetic regulation of metabolic patterns in drug resistant cells. This strategy would provide an approach for reducing exposure to toxic drugs, improving patient quality of life and renewing hope for prolonged control of metastatic PDAC and CRC. This proposal represents a bedside-to-bench-to-bedside project; identifying a shortcoming in how we currently treat PDAC and CRC patients, developing solutions in the lab and ultimately translating such strategies to benefit patients. Citation Format: Glancis Luzeena Raja Arul, Ezequiel Tolosa, Ryan M. Carr, Martin E. Fernandez-Zapico. Modeling evolutionary therapy for GI malignancies [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B002.