Center for Cancer Systems Therapeutics (CaST)

PROJECT SUMMARY Patients with aggressive cancers often present with no pharmacologically actionable mutations and poor or no sensitivity to immune checkpoint blockade, thus deriving only modest improvement in disease-free survival from targeted therapy and immunotherapy. Tumor heterogeneity adds further complexity by fostering reprogramming,

adaptation, selection, and ultimately expansion of drug-resistant cells, as well as emergence of an immunosuppressive tumor microenvironment (TME), both of which are ultimately responsible for patient relapse and poor outcome. Addressing these challenges—i.e., identifying more universal, mechanism-based targets for

pharmacological intervention and assessing their potential value in highly heterogeneous tumors—is critically dependent on the availability of accurate, comprehensive, and cell type-specific molecular interaction networks (cellular networks, hereafter), which underlie both the cell-autonomous behavior of cancer cells and their

interaction with other TME subpopulations. The proposed Cancer Systems Therapeutics (CaST) Center, will continue its highly productive collaboration within the U54 Cancer Systems Biology Center (CSBC) network by extending its successful network-based methodologies—which integrate cutting edge computational advances

and novel experimental technologies, including use of 3D structure and multi-omics-based evidence. This will support studying cancer as a fully integrated system of co-evolving, interacting subpopulations, comprising both molecularly distinct, coexisting malignant cell states as well as non-malignant cell states recruited to the tumor

microenvironment and potentially reprogrammed to implement a pro-malignant, immunosuppressive milieu. The ultimate goal of this proposal is to leverage recent advances by CaST center investigators to elucidate the Mechanism of Action of clinically relevant drugs and late-stage experimental compounds to target individual

subpopulation to either drive combination therapy or to rescue immunotherapy in drug resistant tumors.