PI3K Pathway Inhibitors for Mantle Cell Lymphoma

描述(申请人提供)：非霍奇金淋巴瘤(NHL)目前是美国第五大最常见的癌症。套细胞淋巴瘤(MCL)是非霍奇金淋巴瘤的一种重要类型，其预后非常差，总体生存时间仅为3-4年。MCL的独特之处在于存在t(11；14)(q13；q32)易位，导致磷脂酰肌醇3激酶(PI3K)途径的重要组成部分Cyclin-D1的过度表达。这一途径在调节细胞运动和提高细胞存活率方面具有重要作用。PI3K活性导致哺乳动物雷帕霉素靶标(MTOR)的激活，mTOR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，我们推测PI3K通路的抑制剂在MCL中具有抗肿瘤活性。事实上，我们证明了一种新的mTOR抑制剂CCI-779在38%的复发MCL患者中产生了肿瘤反应。这为在mTOR水平上靶向PI3K通路是有效的提供了重要的临床证据。然而，该途径是复杂的，很明显，靶向PI3K的其他水平。途径可能改善肿瘤的反应。利妥昔单抗是一种针对MCL细胞上CD20的单抗，在约30%的患者中产生单剂肿瘤反应。利妥昔单抗对细胞信号通路的抑制程度与CCI-779不同。我们假设CCI-779的加入将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，以及精心设计的翻译研究，利用这些患者的组织来研究这种组合对PI3K途径蛋白的影响。这项工作被组织为3个具体目标：目标1，确定CCI-779联合利妥昔单抗治疗复发MCL的安全性和有效性。目的：探讨利妥昔单抗与CCI-779联合应用对PI3K通路蛋白的影响及其与患者反应的关系。目的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极有可能改善MCL患者的肿瘤反应，拟议的转译研究将提高我们对这种疾病的发病机制的理解，并有助于未来临床治疗试验的设计。

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.