Targeting Notch3 for the treatment of multiple myeloma

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PROJECT SUMMARY Multiple myeloma (MM) is characterized by the growth and accumulation of monoclonal malignant plasma cells in the bone marrow. MM remains incurable due to its high rate of relapse and the development of drug resistance to therapy. Moreover, MM causes a devastating bone disease, increasing fracture risk and decreasing quality of life. Notch signaling, a pathway mediating cell communication in the MM tumor microenvironment (TME), promotes MM proliferation and MM cell survival and stimulates bone destruction. Notch inhibition decreases MM growth and bone disease in preclinical models, but causes unwanted severe, dose-limiting side effects. The long-term goal of this proposal is to examine Notch receptor 3 (Notch3), a membrane-bound Notch receptor integrating cell-to-cell Notch signals from surrounding cells, as a target to treat MM. The premise of these studies is supported by published and preliminary work showing that 1) cells of TME activate Notch signaling and increase Notch3 expression in MM cells, 2) Notch3 signaling in MM cells promotes MM cell proliferation and bone destruction, and 3) Notch3 signaling dictates MM cell responses to Bortezomib-based therapies. The specific goal of this application is to evaluate the efficacy of targeting Notch3 to decrease tumor growth, mitigate bone disease, and improve therapeutic responses to front-line therapies in MM. The central hypothesis of this proposal is that Notch3 in MM cells integrates TME signals leading to tumor growth, bone destruction, and drug resistance. This hypothesis will be tested in two specific aims. Aim 1 will determine the effects of the pharmacological inhibition of Notch3 on MM growth, bone destruction, and its impact on the transcriptome of TME and MM cells. Aim 2 will evaluate the role of Notch3 signaling in MM cells on TME-induced resistance to Bortezomib-based therapies and identify the underlying molecular mechanisms. To complete these aims, I have assembled a mentoring team of leaders in cancer and drug resistance, bone biology, bioinformatics, and imaging that will allow me to receive a unique multidisciplinary and rigorous training, preparing me to pursue a career as an independent academic scientist.