Abstract 408: Development of a first-in-class notch transcription factor inhibitor CB-103 to overcome resistance to chemotherapy and targeted therapies

Human cancers possess striking ability to develop resistance to Standard of Care (SoC) designed to target specific hallmarks of cancer. This capability to develop resistance is in part due to cancer cell’s ability to activate alternative pathways and modulate tumor microenvironment to enhance cell survival, evade cell death and immunosurveillance. One such mechanism of developing resistance to SoC is the activation of the NOTCH pathway. NOTCH signaling is a developmental pathway which is known to be activated in several human cancers as a key oncogenic hit. In addition to its role as an oncogenic driver, activation of NOTCH is also known to induce resistance to several anti-cancer therapeutics in breast cancer and colorectal cancer. NOTCH signaling is known to cooperate with parallel oncogenic signals to impede activity of several drugs as a single agent. Previous agents targeting the NOTCH pathway upstream of the transcription complex were halted early in clinical development due to dose-limiting toxicities.Here we report activity of a novel first-in-class clinical stage CSL-NICD inhibitor in a panel of cell lines, xenograft and PDX models of human cancers in combination with several chemo and targeted therapies. Guided by in vitro and in vivo studies pre-clinical studies, CB-103 is currently being investigated in clinical trials as a single agent and in combination with SoC. Preliminary pre-clinical and clinical data shows desirable safety and efficacy profile of CB-103 enabling clinical development in combination with several therapeutic agents. Citation Format: Michele Vigolo, Charlotte Urech, Sebastien Lamy, Samarpan Majumder, Lucio Miele, Rajwinder Lehal. Development of a first-in-class notch transcription factor inhibitor CB-103 to overcome resistance to chemotherapy and targeted therapies [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 408.