Targeting DEPTOR in multiple myeloma

描述(由申请人提供)：该提案针对多发性骨髓瘤细胞中TORC复合体中DEPTOR与mTOR结合的潜在靶点。初步结果支持这样的假设，即可以在酵母-杂交高通量筛选中识别出抑制这种结合的化合物。一旦被抑制，我们预计随后会抑制PI3-激酶/AKT通路，并诱导骨髓瘤细胞凋亡。DEPTOR功能对约30%的多发性骨髓瘤克隆患者的生存至关重要。这一特定的患者亚群可以通过对他们的骨髓恶性浆细胞进行现成的临床检测来确定。因此，我们背离了这样的前提，即可以开发出抑制DEPTOR-mTOR结合的已鉴定化合物，用于这些患者的有效靶向治疗。为了进一步将DEPTOR作为一个治疗靶点，我们将测试筛选出的对骨髓瘤细胞的分子效应以及在体外和体内异种移植模型中的抗骨髓瘤效果。

DESCRIPTION (provided by applicant): 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.