Abstract CN03-01: Systematic elucidation and pharmacologic targeting of mechanistic tumor dependencies

Abstract

Abstract Cancer targets fall into three categories: oncoproteins eliciting tumor-specific essentiality due to their direct role in tumorigenesis or tumor maintenance (oncogene dependency) (1), proteins eliciting synthetic lethality with oncogene mutations but having no direct impact on tumorigenesis (non-oncogene codependency) (2), and proteins modulating immunosurveillance (immune-checkpoint dependency) (3). Despite undeniable successes, only 5-11% of cancer patients treated with mutation-based targeted therapy derive objective benefit, based on progression-free survival (4, 5). While immuno-oncology holds great promise, its applicability is also limited by partial efficacy, relapse, and toxicity. As a result, the majority of tumors that are not completely removed by surgery still fail to respond to therapy or relapse to drug-resistant disease. To complement these canonical approaches, we will leverage a framework for the network-based identification and pharmacologic targeting of tumor dependencies implemented by master regulator (MR) proteins, which was developed over the last 8 years by the CTD2 Center at Columbia University. These studies have shown that aberrant activity of a handful of MR proteins—within one or more tumor checkpoint modules (TCM) —is necessary for the stability of cancer phenotypes (6). As a result, genetic or pharmacologic inhibition of individual or synergistic MRs can induce TCM collapse and abrogate tumor viability in a wide range of human malignancies. Specifically, we propose that such a TCM/MR-based framework provides a systematic, mechanistic, and highly efficient platform to elucidate new druggable targets for single-agent and combination therapy, as well as effective molecular biomarkers for patient sensitivity, across most tumor types. The therapeutic strategies prioritized by the proposed framework, on an individual tumor basis, will be rapidly tested in PDX models (N of 1 methodology), leading to rapid identification of candidate drugs and combinations for potential follow-up clinical validation (e.g., in basket trials) (7), consistent with the translational track record of our CTD2 Center (6, 8). We will specifically target malignancies that are either rare and thus poorly characterized, such as atypical/anaplastic meningioma (MEN), or considered untreatable, such as metastatic bladder (BLCA), lung (LUAD), and colon (COAD) adenocarcinoma.