The mTOR kinase functions in two multiprotein complexes, TORC1 and TORC2, and is a tumor promoting protein. We will use a yeast-2-hybrid screen to identify compounds that can interrupt binding of mTOR to its partners within the TORC2 complex as this binding is required for mTORC2 function and appears critical for growth and survival of multiple myeloma tumor cells. These compounds will be further tested and developed as possible anti-myeloma agents. This entails assessment of their molecular effects and in vitro cellular effects in well defined myeloma cell lines and primary tumor cell preparations obtained from bone marrows of patients. We will also identify the compounds' anti-myeloma efficacy in xenograft murine models of myeloma growth. In addition, we will also identify the critical substrates of TORC2 which, when inhibited by our agents, results in apoptosis and inhibited myeloma cell adhesion and migration.
The proposal addresses the mechanism by which the malignancy called multiple myeloma uses a protein complex called TORC2 to maintain its viability and facilitate spread through the skeleton. It designs a plan to identify novel inhibitors of TORC2 and develop them for future therapy in this disease. Multiple myeloma is most frequently found in elderly males. Thus, it is a relatively common life-threatening disease in our veteran population. Thus, we believe our proposal may be able to provide newer treatments to be added to the armamentarium to be used against this serious disease.