Abstract IA002: Functional omics for novel therapeutic combinations in myeloid malignancies

Abstract My research program employs a pipeline of functional approaches for analysis of primary cells from patients with acute myeloid leukemia (AML) and other hematologic malignancies. This platform aims to identify the druggable landscape across hematologic malignancies and prioritize novel combination therapies. The pipeline is comprised of gene knockdown (e.g. siRNA, CRISPR/Cas) and small-molecule libraries to interrogate the genes, pathways, cellular processes, and microenvironmental crosstalk that govern cancer cell growth and drug response, and these functional screens are complemented with deep sequencing. Simultaneous application of these functional approaches with omic data has accelerated our understanding of druggable pathways that contribute to neoplasia. One example of this platform has been our Beat AML 1.0 platform in which we have assessed ex vivo drug sensitivity, whole exome sequencing, and RNA-sequencing for a cohort of nearly 1,000 AML patient samples, which provides a functional genomic landscape for this disease. We have also utilized genome-wide CRISPR screens with overlay of key therapeutic agents in cell line models, and coupling of these genome-wide screen data with the large patient sample dataset has illuminated a diversity of determinants of therapeutic response. In this lecture, I will provide an overview of these functional screening platforms, and I will illustrate strategies of data integration that have enabled rapid discovery and translation of new targeted therapy strategies. This will include discussion of novel biomarkers of drug response in AML, including mutational drivers of drug response and strong correlation of AML tumor cell maturation state with response to a diversity of drugs and drug families. Finally, the lecture will provide examples of the way in which these data can be leveraged to identify novel drug combinations with broad activity and to examine the mechanistic underpinnings of improved combination activity relative to single agents. Collectively, this dataset and integrative approach provide a functional genomic landscape of AML with new biomarkers of drug response. Citation Format: Jeffrey W Tyner. Functional omics for novel therapeutic combinations in myeloid malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr IA002.