Abstract IA21: Elucidating and targeting mechanisms of single-cell state maintenance: From N-of-1 to N-of-1-of-1 studies

Abstract

Abstract We have developed network-based methodologies for the systematic identification, validation, and pharmacologic targeting of a new class of therapeutic targets. These targets comprise Master Regulator proteins, whose concerted aberrant activity within tightly regulated modules (tumor checkpoints) is responsible for the mechanistic implementation and maintenance of specific tumor cell states. By leveraging these methodologies, we have developed OncoTreat, a NY CLIA-certified test that leverages large-scale drug-perturbation assays to systematically identify drugs and drug combinations whose mechanism of action is specifically effective in abrogating tumor checkpoint activity, on an individual patient basis. These tests have shown 60% validation rate across 39 predicted drugs that were validated in PDX models from patients who had failed multiple standard-of-care therapies. In this talk, we will introduce these concepts and then demonstrate their application to elucidating drugs capable of targeting transcriptionally distinct tumor niches by single-cell analysis (N-of-1-of-1 studies). In particular, we will show identification and validation, in vivo, of drugs targeting the stemlike progenitor niche of breast adenocarcinomas and the four transcriptionally distinct single-cell subtypes identified in glioblastoma patients. Citation Format: Andrea Califano. Elucidating and targeting mechanisms of single-cell state maintenance: From N-of-1 to N-of-1-of-1 studies [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA21.