mTOR Inhibition as a Therapeutic Target in Myeloma

mTOR 抑制作为骨髓瘤的治疗靶点

• 批准号: 6887130
• 负责人: Sherif S Farag
• 金额: $ 26.91万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-17 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887130
• 关键词: antineoplastics; biological signal transduction; cell growth regulation; cell proliferation; clinical research; clinical trial phase II; human subject; human therapy evaluation; multiple myeloma; neoplasm /cancer chemotherapy; patient oriented research; pharmacokinetics; relapse /recurrence

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.

描述（由申请人提供）：多发性骨髓瘤（MM）的治疗仍不令人满意。传统的化疗，包括干细胞支持的大剂量治疗，延长了生存期，但本质上是姑息性的，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，并受肿瘤抑制基因产物PTEN的负调控。PTEN可能在某些MM病例中发生突变，并通过PI3K/Akt导致信号通路增加。我们研究了使用CCI-779抑制PI3K/Akt/mTOR通路作为MM的治疗靶点，CCI-779是一种mTOR抑制剂，参与将有丝分裂信号与细胞周期转运结合的下游信号传导。具体而言，我们建议1)在复发或难耐MM患者中开展CCI-779的II期试验以评估临床反应，2)前瞻性研究MM中PTEN突变或基因沉默的频率，并将其目前的突变和沉默与CCI-779的临床反应联系起来，因为PTEN的表达似乎会影响细胞对体外药物的敏感性。3) CCI-779对外周血单个核细胞的体内药效学活性与对骨髓瘤细胞的体内药效学活性以及治疗患者血浆药物水平的相关性。本研究结果对MM的治疗具有重要意义，并可能为该疾病的治疗开辟新的途径。