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: 9978752
• 负责人: THOMAS M ROBERTS
• 金额: $ 104.98万
• 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/9978752
• 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.

项目概要/摘要 在研究不同肿瘤类型的 PI3 激酶亚型依赖性时，我们得出了一个极其令人惊讶的结果 现在发现这一发现具有相当大的临床重要性。这一发现构成了本次 OIA 的基础 应用。我们发现，由 PTEN 肿瘤抑制因子缺失驱动的肿瘤是独一无二的 依赖于 PI3 激酶的 p110β 亚型。这一发现可能解释了为什么 PI3K 抑制剂首先在 PTEN 缺失肿瘤在临床上失败了，因为它们是较差的 p110β 抑制剂。新的 p110b 特定化合物是 现在显示出临床前景。试图理解独特耦合的分子机制 PTEN缺失导致p110β激活，我们发现了一套分子机制，这不仅解释了 p110β 是如何响应 PTEN 缺失而被激活的，同时也表明了为什么相同的肿瘤可能会很快 变得部分甚至完全抵抗 PI3K 抑制。值得注意的是，相同的机制清楚地表明 其他药物靶点，可以而且应该与 PTEN 缺失肿瘤中的 PI3K 联合攻击。我们非常 最近的数据确定了 2 种与 p110β 相互作用的蛋白质，而不是与 p110α 相互作用，形成正反馈 在没有 PTEN 的情况下循环。这些蛋白质之一是小型 ras 家族 GTP 酶，称为 Rac，它 与 p110β 相互作用，但不与 p110α 相互作用。我们最近表明 Rac 将 p110b 定位于脂筏，在那里它 被激活。因此，Rac 是 p110β 的上游激活剂。然而 Rac 家族成员的独特之处在于 它们的激活剂 Rac GEF 由 PI3K 的磷酸肌醇产物激活。因此 Rac 也是一个 p110β 的下游效应子。 Rac 和 p110β 的相互作用构成了正向的定义 反馈循环。然而，这仍然没有解决 Rac/p110β 反馈环路是如何启动的——什么激活了 p110β/Rac 位居首位。我们发现激活事件依赖于小接头蛋白 CRKL 也是一种 p110β 特异性结合蛋白。 CRKL 通过 SRC/p130Cas 信号传导激活 PTEN 丢失也会激活级联反应。值得注意的是，SRC 信号传导使细胞对 PI3K 抑制具有抵抗力。 最后也是最令人兴奋的是，我们发现 p110b 抑制剂与免疫检查点阻断具有协同作用。我们 已生成的数据已显示 SRC RAC PAK（RAC 的另一个下游目标）的抑制剂 脂筏形成和免疫检查点都可以在体外与 p110b 抑制剂很好地结合，并且在某些情况下 案例，体内。这笔赠款一方面将侧重于对新药组合进行更严格的测试，另一方面 另一方面，进一步完善我们对 PTEN 损失影响的机制理解，以产生甚至 更好的联合治疗。