LAUSR

Cancer immunotherapy with immune checkpoint inhibitors (ICI) has shown durable clinical benefits in patients with immune-hot tumors. However, the majority of cancers are characterized by an immune-cold tumor microenvironment, which are refractory to ICI therapy. Targeting of tumor synthetic vulnerabilities due to genomic alterations is another promising approach that has proven effective in the clinic (e.g. PARP inhibitors in BRCA-mutant tumors). Here, we aimed to identify therapeutic targets that have dual liabilities in tumor cell survival and the evasion of anti-tumor innate immune responses. Applying machine learning approaches to a manually curated compendium of public and proprietary datasets, we identified and validated several genes with a high potential of conferring tumor-intrinsic cell survival and blocking of innate pro-inflammatory responses in immune-cold tumors. The targeting of these genes induced robust cell killing and activation of innate immune response pathways in specific molecularly-defined tumor populations, including immune-cold cells. A series of highly potent small molecule compounds were established against these targets using structure-based design, which shows robust in vitro and in vivo target engagement and favorable cytotoxic and phenotypic profiles across a large panel of cancer cell lines and PDXs. Collectively, this therapeutic program shows significant promise in treating a multitude of solid tumors as a monotherapy and in combination with currently approved immune therapies. Citation Format: Daniel Ciznadija, Gemechis Degaga, Abdul Mondal, Maxwell Hillbert, Cong Chen, Bikash Debnath, Sonam Mehrotra, Brandon Jones, Ralph Rivero, Kakajan Komurov. Targeting tumor synthetic vulnerabilities and immune evasion mechanisms with CO-1002 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1599.