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）现在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，因为它具有非常差的预后，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，其导致细胞周期蛋白-D1的过度表达，细胞周期蛋白-D1是磷脂酰肌醇3激酶（PI 3 K）途径的重要组分。该途径在介导细胞运动性和增强细胞存活方面是重要的。PI 3 K活性导致雷帕霉素的哺乳动物靶标（mTOR）的活化，所述mTOR是细胞存活的关键细胞调节剂。由于MCL细胞过度表达细胞周期蛋白D1，我们假设PI 3 K通路的抑制剂在MCL中具有抗肿瘤活性。事实上，我们证明了CCI-779，一种新的mTOR抑制剂，在38%的复发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水平靶向PI 3 K通路可能是有效的。然而，该途径是复杂的，很明显，靶向其他水平的PI 3 K。这可能会改善肿瘤反应。利妥昔单抗是一种单克隆抗体，靶向MCL细胞上的CD 20，并在约30%的患者中产生单药肿瘤反应。利妥昔单抗抑制细胞信号通路在不同的水平比CCI-779。我们假设加入CCI-779将增强利妥昔单抗的抗肿瘤活性。我们建议在II期研究（N 038 H）中研究该组合，沿着精心设计的转化研究，利用这些患者的组织研究该组合对PI 3 K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。目的2，研究利妥昔单抗和CCI-779联合应用对PI 3 K通路蛋白的影响，并将这些变化与患者中观察到的反应联系起来。目的3，研究阻断PI 3 K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，拟议的转化研究将提高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。