PI3K Pathway Inhibitors for Mantle Cell Lymphoma

套细胞淋巴瘤的 PI3K 通路抑制剂

• 批准号: 6998325
• 负责人: Thomas E. Witzig
• 金额: $ 25.64万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-18 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6998325
• 关键词: B cell lymphoma; antineoplastics; biological signal transduction; cell line; cell migration; clinical research; clinical trial phase II; combination chemotherapy; cyclins; drug interactions; drug screening /evaluation; human subject; human therapy evaluation; kinase inhibitor; microarray technology; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; neoplastic growth; phosphatidylinositol 3 kinase; protein structure function; sirolimus

DESCRIPTION (provided by applicant): Non-Hodgkin's Lymphoma (NHL) is now the fifth most common cancer in the United States. Mantle cell lymphoma (MCL) is an important type of NHL because it has a very poor prognosis with an overall survival of only 3-4 years. MCL is unique in that the cells have a t(11;14)(q13;q32)translocation that results in over-expression of cyclin-D1, an important component of the phosphotidyl inositol 3 Kinase (PI3K) pathway. This pathway is important in mediating cell motility and in enhancing cell survival. PI3K activity results in activation of the mammalian target of rapamycin (mTOR) a key cellular regulator of cell survival. Since MCL cells over-express cyclin-D1, we hypothesized that inhibitors of the PI3K pathway would have anti-tumor activity in MCL. Indeed, we demonstrated that CCI-779, a novel mTOR inhibitor, produced tumor responses in 38% of relapsed MCL patients. This provides important clinical evidence that targeting the PI3K pathway at the level of mTOR can be effective. However, the pathway is complex and it is apparent that targeting other levels of the PI3K. pathway may improve the tumor response. Rituximab is a monoclonal antibody that targets CD20 on MCL cells and produces single agent tumor responses in about 30% of patients. Rituximab inhibits cell signaling pathways at different levels than CCI-779. We hypothesize that the addition of CCI-779 will enhance the anti-tumor activity of rituximab. We propose to study this combination in a phase II study (N038H) along with carefully designed translational research studies that utilize tissue from these patients to investigate the effects of the combination on PI3K pathway proteins. This work is organized into 3 specific aims: Aim 1, to determine the safety and efficacy of the combination of CCI-779 with rituximab in patients with relapsed MCL. Aim 2, to investigate the effect of the combination of rituximab and CCI-779 on PI3K pathway proteins and relate the changes to responses observed in the patients. Aim 3, to study the effect of inhibition of the PI3K pathway on migration of MCL cells. This unique clinical trial has a high likelihood of improving tumor responses in MCL patients and the proposed translational research will improve our understanding of the pathogenesis of this disease and aid in the design of future clinical treatment trials.

描述（由申请人提供）：非霍奇金淋巴瘤 (NHL) 目前是美国第五大常见癌症。套细胞淋巴瘤（MCL）是NHL的一种重要类型，预后极差，总生存期仅为3-4年。 MCL 的独特之处在于细胞具有 t(11;14)(q13;q32) 易位，导致细胞周期蛋白-D1 过度表达，周期蛋白-D1 是磷脂酰肌醇 3 激酶 (PI3K) 途径的重要组成部分。该途径对于介导细胞运动和增强细胞存活很重要。 PI3K 活性导致哺乳动物雷帕霉素靶点 (mTOR) 的激活，雷帕霉素靶点是细胞存活的关键细胞调节因子。由于 MCL 细胞过度表达 cyclin-D1，我们假设 PI3K 通路抑制剂在 MCL 中具有抗肿瘤活性。事实上，我们证明了 CCI-779（一种新型 mTOR 抑制剂）在 38% 的复发性 MCL 患者中产生了肿瘤反应。这提供了重要的临床证据，表明在 mTOR 水平上靶向 PI3K 通路可能是有效的。然而，该途径很复杂，并且明显针对 PI3K 的其他水平。途径可能改善肿瘤反应。利妥昔单抗是一种单克隆抗体，靶向 MCL 细胞上的 CD20，并在约 30% 的患者中产生单药肿瘤反应。 Rituximab 与 CCI-779 相比，在不同水平上抑制细胞信号传导通路。我们假设CCI-779的添加会增强利妥昔单抗的抗肿瘤活性。我们建议在 II 期研究 (N038H) 中研究这种组合，以及精心设计的转化研究，利用这些患者的组织来研究该组合对 PI3K 通路蛋白的影响。这项工作分为 3 个具体目标： 目标 1，确定 CCI-779 与利妥昔单抗联合治疗复发性 MCL 患者的安全性和有效性。目标 2，研究利妥昔单抗和 CCI-779 组合对 PI3K 通路蛋白的影响，并将这些变化与在患者中观察到的反应联系起来。目标3，研究抑制PI3K通路对MCL细胞迁移的影响。这项独特的临床试验很有可能改善 MCL 患者的肿瘤反应，拟议的转化研究将增进我们对这种疾病发病机制的理解，并有助于设计未来的临床治疗试验。