Therapeutic Targeting of Breast Cancer Tumor Initiating Cells

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PROJECT ABSTRACT Triple Negative Breast Cancer (TNBC), if considered its own disease type, would rank as the 5th leading cause of cancer deaths in women in the USA. The main systemic treatment option for these patients in the adjuvant setting is multi-agent chemotherapy, and now since early 2019, immunotherapy plus chemotherapy is an option for PDL1-positive metastatic patients. TNBC is also known to be biologically heterogeneous, with multiple genomically-defined subtypes present. We hypothesize that much of this heterogeneity actually represents cellular plasticity, and that some TNBC subtypes can actually morph from one subtype into another. We hypothesize that this plasticity is a key determinant of chemotherapy responsiveness, immune checkpoint inhibitor sensitivity, and metastatic potential. Furthermore, we hypothesize that if we are able to keep, or promote, a tumor into the basal-like state, there may be both a change in the immune microenvironment and increased therapy sensitivity. We will test these hypotheses by using novel combinations of drugs, in vitro screens, and in vivo testing of metastasis vs primary tumor sensitivity using Genetically Engineered Mouse models and human tumor specimens.