The long-term objectives of this project are to develop innovative therapies for patients with high-risk or refractory CNS lymphomas. Current genotoxic strategies used in clinical trials have achieved a plateau in anticipated progression-free survival for newly- diagnosed patients. There is a clear unmet need for the development and integration of more effective therapies for the greater than 40% of patients who progress during the first six months with conventional therapy, as well as for the increasing proportion of older patients who do not tolerate high-dose chemotherapy or brain irradiation. We propose an innovative strategy to evaluate cutting-edge targeted therapies that we hypothesize will disrupt key survival pathways in high-risk CNS lymphoma tumors. In addition, we will evaluate these candidate approaches using novel, patient-derived CNS lymphomas generated from chemotherapy-refractory specimens. Our general strategy is to comprehensively evaluate the efficacy of four candidate targeted therapies in preclinical mouse models of patient-derived CNS lymphomas. We will also test the hypothesis that these agents may have collateral effects on the innate immune response mediated by tumor-associated macrophages and microglia. The specific aims are to determine the response of the pharmacologic disruption of candidate key survival pathways, BCL6, MYC, JAK/STAT and/or Btk pathways in CNS lymphoma, using novel, patient-derived, xenograft mouse models of CNS lymphoma. We will also determine the pharmacodynamic impact of these agents on tumor physiology and metabolism. In addition, we will evaluate these agents in combination with relevant established pharmaceutical compounds that have demonstrated efficacy in CNS lymphoma and in these mouse models: rituximab, temozolomide, lenalidomide. Finally, we will test the hypothesis that lead candidates evaluated may have collateral impact on the myeloid response within the CNS and potentially synergize with or attenuate the efficacy of established agents. Results of these studies will facilitate the development of innovative therapeutic strategies that address an unmet need for CNS lymphoma patients and accelerate the evaluation of rationally-defined, potent combinations in early phase trials. Furthermore, these studies will have implications for a variety of disorders in which immune surveillance as well as antibody-dependent cell-mediated cytotoxicity are important means of disease control.