mTOR Inhibition as a Therapeutic Target in Myeloma

描述(申请人提供)：多发性骨髓瘤(MM)的治疗仍然不令人满意。常规化疗，包括大剂量的干细胞支持治疗，可以延长生存期，但本质上是姑息的，这表明需要新的药物。针对骨髓瘤细胞增殖中重要的特定细胞分子靶点的新方法可能会改善结果。PI3K/Akt/mTOR通路介导骨髓瘤细胞的生长和存活，并受抑癌基因产物PTEN的负调控。在某些MM中，PTEN可能发生突变，并通过PI3K/Akt导致信号增强。我们使用mTOR的抑制剂CCI-779来研究抑制PI3K/Akt/mTOR通路作为多发性骨髓瘤的治疗靶点，CCI-779参与了连接有丝分裂信号和细胞周期传递的下游信号传递。具体地说，我们建议1)在复发或难治性MM患者中进行CCI-779的II期试验以评估临床疗效，2)前瞻性研究PTEN突变或基因沉默在MM中的频率，并将它们目前的突变和沉默与临床对CCI-779的反应相关，因为PTEN的表达似乎在体外影响细胞对该药物的敏感性，以及3)CCI-779对外周血单核细胞和骨髓瘤细胞的体内药效学活性，以及与接受治疗的患者的血浆药物水平相关。本研究结果对多发性骨髓瘤的治疗具有重要意义，并可能为多发性骨髓瘤的治疗开辟新的途径。

DESCRIPTION (provided by applicant): Therapy for multiple myeloma (MM) remains unsatisfactory. Conventional chemotherapy, including high-dose treatment with stem cell support, prolongs survival but is essentially palliative, indicating the need for novel agents. Novel approaches directed at specific cellular molecular targets important in the proliferation of myeloma cells may improve outcome. The PI3K/Akt/mTOR pathway mediates the growth and survival of myeloma cells, and is negatively modulated by PTEN, a product of a tumor suppressor gene. PTEN may be mutated in some cases of MM, and lead to increased signaling through PI3K/Akt. We investigate the inhibition of the PI3K/Akt/mTOR pathway as a therapeutic target in MM using CCI-779, an inhibitor of mTOR, involved in downstream signaling that couples mitogenic signals with cell cycle transit. Specifically, we propose 1) to conduct a phase II trial of CCI-779 in relapsed or refractory MM patients to assess the clinical response, 2) prospectively study the frequency of PTEN mutations or gene silencing in MM, and correlate their present mutations and silencing with clinical response to CCI-779, as PTEN expression appears to influence a cell's sensitivity to the drug in vitro, and 3) correlate the in vivo pharmacodynamic activity of CCI-779 on peripheral blood mononuclear cells with that on myeloma cells, and with plasma levels of the drug in patients treated. The results of this research have important significance for the treatment of MM and may lead to a novel therapeutic approach in this disease.