Abstract 2326: Preclinical characterization of MTB-9655, a first-in-class, clinical stage ACSS2 inhibitor

Abstract

Abstract ACSS2 is a nucleo-cytoplasmic enzyme that converts acetate into Acetyl-CoA. In many tumor types ACSS2 is dramatically upregulated in response to the hypoxic and lipid-depleted conditions often encountered in the tumor microenvironment. In these conditions, ACSS2 allows tumor cells to switch to acetate as key carbon source to meet their anabolic and energetic needs and thereby they become dependent on both acetate and ACSS2. MTB-9655 is a novel, potent and selective ACSS2 inhibitor discovered at Metabomed. It is currently in Phase I clinical investigation on patients with tumors with high levels of ACSS2. The antitumor effect of MTB-9655 was characterized in a number of PDX models across various tumor types. PDX tumors that exhibit over 50 TPM copies of ACSS2 mRNA showed significant sensitivity to ACSS2 inhibition in vivo. TCGA analyses suggests that most GU tumors, such as hepatocellular, gastric, colorectal show high frequency of ACSS2 upregulation and therefore present an opportunity for treatment with MTB-9655. In addition, PDX studies revealed a significant combination effect with cisplatin and gemcitabine. This opens opportunities for combination treatments of several GU cancers expressing high levels of ACSS2, such as ovarian and breast cancers.As a potential PD biomarker assay, 11C acetate PET imaging was explored preclinically in tumor-bearing mice as a way to assess inhibition of acetate flux in the presence of ACSS2 inhibitor. MTB-9655 resulted in robust inhibition of 11C acetate uptake in tumors in a dose-dependent manner opening the possibility of using 11C acetate PET as a clinical PD biomarker. Citation Format: Andreas Goutopoulos, Iris Amanati, Ali Fattaey, Avital Hay-Koren, Philippe Nakache, Omri Erez, Dimitri Kovalerchik, Dikla Paz, Simone Botti, Hannah Oppenheimer, Irit Fainer. Preclinical characterization of MTB-9655, a first-in-class, clinical stage ACSS2 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2326.