Preliminary work indicates the mTOR-binding protein DEPTOR is a potential molecular target for therapy in multiple myeloma. It is specifically upregulated in this disease and its silencing is lethal to myeloma cells. We, thus, identified a potential DEPTOR inhibitor in a high-throughput drug screen. The inhibitor is effective in myeloma cells with the expected molecular alterations and induction of death. In this proposal we plan to further develop this inhibitor. We will generate biochemical derivatives with the aim of enhancing the therapeutic index of DEPTOR inhibitors, identify the mechanism of action of where the inhibitors first bind in myeloma cells, ascertain possible toxicity to normal tissues in mice with deleted DEPTOR expression and assess possible interactions with other anti-myeloma therapeutics that are used in the clinic. We will also test the effect of DEPTOR on flux through the pentose phosphate shunt. Our expectation is that these new drugs will be important additions to the armamentarium used in myeloma patients and, furthermore, they will be specifically tailored to patients with tumors that have high DEPTOR expression.
The proposal addresses the potential therapeutic utility of inhibitors that target the protein DEPTOR in the malignancy called multiple myeloma. This protein is singularly activated in multiple myeloma tumor cells and its inhibition results in death of the tumor cells. This proposal designs a plan to develop these DEPTOR inhibitors for future use in the clinic. Multiple myeloma is most frequently found in elderly males and is incurable. 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.