Abstract 1004: Defining stearoyl-CoA desaturase 1 as a molecular therapeutic target against cholangiocarcinoma

Abstract

Abstract Cancer cells increase lipid metabolism by up-regulation lipogenic enzymes such as stearoyl-CoA desaturase 1 (SCD1). It is the rate-limiting enzyme in the de novo synthesis of fatty acids (FAs), catalyzing the conversion and biosynthesis of saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). We developed SSI-4, a novel highly specific SCD1 inhibitor. The anti-tumor activity ofSSI-4 was examined against different cholangiocarcinoma (CCA) models that included human and mouseCCA cell lines, CCA patient-derived xenografts (PDX) NOD SCID gamma (NSG) mouse models, and CCA PDX derived organoids. Using cell proliferation assay, we examined twelve CCA cell lines and 4 were very sensitive to SSI-4 (1-40 nM IC50). The remaining CCA cell lines showed moderate to no sensitivity to SSI-4. Studies at the protein level have shown that SCD1 is present in both sensitive and non-sensitive cells. Thus, SCD1 must be present in sensitive cells but is not predictive of response to an SCD1 inhibitor. In an effort to identify biomarkers predicting response to therapy, we performed assays, such as lipid, lactate, or energy phenotype which identified elevated lactate and unsaturated fatty acid levels as well as a glycolytic energy phenotype. In vivo, CCA PDX models have demonstrated that SSI-4strongly inhibited tumor growth. Immunohistochemical analysis of CCA tumors revealed elevated glycolytic genes in sensitive cells and thus, a potential predictive biomarker. We are currently pursuing a better understanding of the relationship between glycolysis and fatty acid synthesis/metabolism. We are also testing novel combination therapy of SSI-4 with the standard of care and other drugs to develop novel treatments for CCA. Using CCA PDX derived organoids showed synergistic antitumor activity of SSI-4in combination with cancer standard of care drugs such as gemcitabine and cisplatin. Collectively, we expect to develop a biomarker-driven selection of CCA patients sensitive to SCD1 inhibitors and novel SSI-4 combination therapy leading to improved patient survival. Citation Format: Justyna J. Gleba, Laura A. Marlow, Erin E. Miller, James L. Miller, Aylin Alasonyalilar-Demirer, Yi Guo, Kabir Mody, Lewis R. Roberts, Steven R. Alberts, Mark J. Truty, Tushar C. Patel, John A. Copland. Defining stearoyl-CoA desaturase 1 as a molecular therapeutic target against cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1004.