Integrating targeted therapy and immunotherapy to break through cancer

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Project Summary/Abstract Research in our laboratory is centered on understanding the diverse signaling networks regulating essential cellular processes in cancer, and how these affect the interplay between tumor, stromal and immune cells. Our research program combines a multi-pronged approach to advance basic scientific discoveries to pre-clinical, translational research and, ultimately, to clinical development. Our major goal is to develop safe and effective therapies for treating patients with cancer. Specifically, our research program will i) investigate the role of PI3K/PTEN signaling in shaping immune response in breast and prostate cancer, ii) investigate cellular and molecular mechanisms by which the immune system affects response to targeted therapies in breast cancer, and iii) investigate mechanisms of metastatic spread to the brain and treatment strategies against breast cancer brain metastasis (BCBM). To this end, we will capitalize on our expertise on signal transduction and pharmacology applied to genetically-engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) to conduct multi-omics studies, as well as detailed mechanistic studies aimed to significantly advance our understanding of tumorigenesis, immune evasion and therapeutic resistance. For each of these aims, we will carry out studies focused on cellular and molecular mechanisms underlying biological functions and response to therapies, and will also evaluate rational combinations of targeted therapies and immune modulators in clinically relevant mouse models. We will focus on how distinct oncogenic alterations differentially affect the anti- tumor immune response, and will place a particular emphasis on understanding how the interplay between tumor and immune cells affects therapeutic outcome. We have and will continue to develop novel GEMMs and PXD models suitable for these studies, in addition to incorporating powerful new technologies to maximize the potential impact of our research. We have the experience, expertise and support to carry out these studies, and we are confident that we can continue to make significant contributions to the fields of cancer biology and immuno-oncology, and to the many patients and families afflicted by this disease.