Summary Current chemotherapeutic agents have improved multiple myeloma (MM) patient survival. However, MM remains incurable due to high rate of disease relapse that originate from dormant MM clones resistant to therapy. Further, anti-MM therapies have minor effects on repairing MM-induced bone disease, a leading cause of morbidity and mortality in MM patients. Thus, disease relapse and bone disease remain major unmet medical needs that require innovative approaches to effectively treat MM. The overall goal of this proposal is to evaluate the efficacy of novel bone-targeted therapies blocking key interactions between MM cells and cells of the tumor niche to stop the progression of MM in bone. We will focus on Notch and Wnt signaling, two major signaling pathways mediating tumor-host microenvironment communication. In studies leading to this application, we generated a bone-targeted Notch inhibitor (BT-GSI) that selectively decreases Notch signaling in bone. Inhibition of Notch communication in the tumor niche with BT-GSI reduced MM growth and decreased osteoclast number and bone destruction. Importantly, BT-GSI circumvented the gut toxicity that limits the use of Notch inhibitors in the clinic. Further, we found that interactions between MM cells and osteocytes increase the expression of Sclerostin, a local Wnt signaling antagonist that inhibits osteoblast bone forming function. Blockade of Sclerostin using neutralizing antibodies (Scl-Ab) prevented MM-induced bone disease by increasing osteoblasts and stimulating new bone formation. Importantly, our work leading to this application showed that interactions between MM cells and osteoblasts maintain MM cells in a dormant state, while interactions with osteoclasts promote their reactivation into proliferating MM cells. Based on these preliminary findings, we propose that combined bone- directed therapies inhibiting Notch and activating Wnt signaling will 1) decrease MM growth, 2) prevent reactivation of MM dormant cells, and 3) repair damaged bone, while reducing systemic toxic effects. This hypothesis will be advanced by pursuing specific aims that employ established mouse models of MM-induced bone disease and MM dormancy and new pharmacologic tools targeted to the tumor niche. Two aims are proposed. Aim 1 will determine the pharmacokinetic, pharmacodynamic, and safety profiles of our bone-targeted Notch inhibitor BT-GSI. Aim 2 will examine the effects of combined bone-targeted inhibition of Notch signaling (BT-GSI) and activation of the Wnt pathway (Scl-Ab) on tumor growth, bone repair, and MM cell dormancy.