Maximizing the Effectiveness of PI3K Inhibitors in the Treatment of Pten null Cancers

最大化 PI3K 抑制剂治疗 Pten 无效癌症的有效性

• 批准号: 9816457
• 负责人: THOMAS M ROBERTS
• 金额: $ 92.54万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9816457
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adaptor Signaling Protein; BCAR1 gene; Binding Proteins; CRKL gene; CRKL protein; Cells; Clinic; Clinical; Combined Modality Therapy; Data; Defect; Dependence; Drug Targeting; Effectiveness; Event; Family; Family member; Feedback; Grant; Growth Factor Receptors; Guanosine Triphosphate Phosphohydrolases; In Vitro; Malignant Neoplasms; Membrane Microdomains; Molecular; Oncogenes; PTEN gene; Pharmaceutical Preparations; Phosphatidylinositide 3-Kinase Inhibitor; Phosphatidylinositols; Protein Isoforms; Proteins; Resistance; Signal Transduction; Testing; Tumor Suppressor Proteins; Work; immune checkpoint; immune checkpoint blockade; in vivo; inhibitor/antagonist; novel drug combination; response; tumor

Project Summary/Abstract In studying the PI3 Kinase isoform dependence of different tumor types, we made an extremely surprising finding that now turns out to have considerable clinical importance. This finding forms the basis for this OIA application. We discovered that tumors driven by the loss of the PTEN tumor suppressor are uniquely dependent on the p110β isoform of PI3 Kinase. This finding likely explains why PI3K inhibitors first tested on PTEN null tumors failed in the clinic, as they were poor p110β inhibitors. New p110b specific compounds are now showing clinical promise. In attempting to understand the molecular mechanisms that uniquely couple PTEN loss to p110β activation, we have uncovered a set of molecular mechanisms, which not only explains how p110β is activated in response to PTEN loss but also suggests why the same tumors might quickly become partially or even totally resistant to PI3K inhibition. Notably the same mechanisms clearly suggest other drug targets, which can and should be attacked in combination with PI3K in PTEN null tumors. Our very recent data identify 2 proteins that uniquely interact with p110β, and not with p110α, form a positive feedback loop in the absence of PTEN. One of these proteins is the small ras family GTPase known as Rac, which interacts with p110β but not p110α. We have recently shown that Rac localizes p110b to the lipid rafts where it is activated. Thus Rac is an upstream activator of p110β. However Rac family members are unique in that their activators, the Rac GEFs, are activated by the phosphoinositide products of PI3Ks. Thus Rac is also a downstream effector of p110β. The interactions of Rac and p110β constitute the very definition of a positive feedback loop. However, this leaves open how the Rac/p110β feedback loop is initiated- what activates p110β/Rac in the first place. We have found that the activation event is dependent the small adapter protein CRKL which is also a p110β specific binding protein. Activation of CRKL occurs via a SRC/p130Cas signaling cascade that is also activated by PTEN loss. Notably SRC signaling renders cells resistant to PI3K inhibition. Finally and most exciting we have found that p110b inhibitors synergize with immune checkpoint blockade. We have generated data already showing the inhibitors of SRC RAC PAK (another downstream target of RAC) lipid raft formation and immune checkpoints can all combine well with p110b inhibitors in vitro, and in some cases, in vivo. This grant will focus more rigorous testing of new drug combinations on the one hand and on the other hand, further refining our mechanistic understanding of the effects of PTEN loss to generate even better combination therapy.

项目摘要/摘要 在研究不同肿瘤类型的PI3激酶同工型依赖性时，我们做出了一个极其令人惊讶的 发现现在发现这具有相当大的临床重要性。这一发现构成了这个OIA的基础 应用。我们发现，由PTEN肿瘤抑制剂丧失驱动的肿瘤是独特的 取决于PI3激酶的P110β同工型。这一发现可能解释了为什么PI3K抑制剂首次测试 PTEN无肿瘤在诊所失败，因为它们是P110β抑制剂较差。新的P110B特定化合物是 现在表现出临床承诺。试图理解独特夫妇的分子机制 PTEN损失了P110β激活，我们发现了一组分子机制，这不仅解释了 如何响应PTEN损失而激活P110β，但也暗示了为什么同一肿瘤可能会迅速 部分甚至完全抵抗PI3K抑制作用。值得注意的是相同的机制明确表明 其他药物靶标可以并且应该与PTEN无肿瘤中的PI3K结合攻击。我们的 最近的数据鉴定了2种与p110β唯一相互作用而不是与p110α相互作用的蛋白质，形成了正反馈 在没有PTEN的情况下循环。这些蛋白质之一是RAS小型GTPase，称为RAC，它 与p110β相互作用，但没有p110α。我们最近表明，RAC将P110B定位于脂质筏 被激活。该RAC是p110β的上游激活剂。但是RAC家庭成员是独一无二的 它们的活化剂RAC GEFS被PI3K的磷酸肌醇产物激活。那个RAC也是 p110β的下游效应子。 RAC和P110β的相互作用构成了阳性的定义 反馈循环。但是，这留下了如何启动RAC/P110β反馈回路的开放 - 什么激活 首先是P110β/RAC。我们发现激活事件取决于小型适配器蛋白 CRKL也是P110β特异性结合蛋白。 CRKL的激活是通过SRC/P130CAS信号传导发生的 级联也因PTEN损失而激活。 SRC信号传导显着，使细胞具有抗PI3K抑制作用。 最终，最令人兴奋的是，我们发现P110B抑制剂与免疫障碍物封锁协同作用。我们 已经生成已经显示SRC RAC PAK抑制剂的数据（RAC的另一个下游目标） 脂质筏的形成和免疫检查点可以很好地与P110B抑制剂在体外结合，在某些情况下都可以很好地结合 病例，体内。该赠款一方面将重点进行更严格的新药组合测试 另一方面，进一步完善了我们对PTEN损失影响的机械理解，即使 更好的组合疗法。