The proposal addresses the potential of targeting the binding of DEPTOR to mTOR in TORC complexes in multiple myeloma cells. The preliminary results support the hypothesis that compounds can be identified in a yeast-hybrid high throughput screen that inhibit this binding. Once inhibited, we anticipate a subsequent dampening of the PI3-kinase/AKT pathway and induction of myeloma cell apoptosis. DEPTOR function is critical for survival of a subset of multiple myeloma clones consisting of approximately 30% of patients. This specific subset of patients can be identified by readily available clinical testing on their marrow malignant plasma cells. Thus, we part from the premise that identified compounds that inhibit DEPTOR-mTOR binding could be developed for effective targeted therapy for these patients. To further address DEPTOR as a therapeutic target, we will test the screening positive 'hits'for molecular effects in myeloma cells as well as anti-myeloma efficacy in vitro and in vivo in xenograft models.
The goal of the proposal is to identify new therapies that can improve the management of multiple myeloma patients. Multiple myeloma is a malignant disease of plasma cells. It is incurable with a median survival of 4-5 years. Thus, new therapies are sorely needed. We believe we can identify new agents with efficacy in the disease through our novel screening procedure where >150,000 chemicals are tested rapidly by a robotic assay. We have already several such drugs with great potential in this serious disease.
|Shi, Yijiang; Frost, Patrick; Hoang, Bao et al. (2014) MNK1-induced eIF-4E phosphorylation in myeloma cells: a pathway mediating IL-6-induced expansion and expression of genes involved in metabolic and proteotoxic responses. PLoS One 9:e94011|
|Bardeleben, Carolyne; Sharma, Sanjai; Reeve, Joseph R et al. (2013) Metabolomics identifies pyrimidine starvation as the mechanism of 5-aminoimidazole-4-carboxamide-1-*-riboside-induced apoptosis in multiple myeloma cells. Mol Cancer Ther 12:1310-21|