Bone Targeting Approach for Bone Cancers

Multiple myeloma (MM) is a plasma cell neoplasm and the second most common adult hematologic malignancy. It arises in the bone marrow where it causes multiple foci of localized bone destruction with associated bone pain and increased risk of fractures. The etiology of MM has not been defined and the disease remains incurable. Bortezomib (Btz) is a FDA-approved drug for the treatment of patients with MM and also for mantle cell lymphoma. However, serious side effects of Btz limit its utility clinically.

To overcome this limitation, we conjugated Btz to a bisphosphonate (BP) residue using a novel chemical linker to generate to a bone-targeted Btz (BP-Btz) and demonstrated its efficacy in a mouse model of MM. We will design and synthesize various BP-Btz analogs and examine their distribution, release kinetics and the effects of BP-Btz on myeloma tumor burden and associated bone destruction in a mouse model of MM. Our study will provide:

1. Preclinical information on the utility of bone-targeting Btz as a new approach to treat MM
2. A rationale for developing other bone targeted drugs

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