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.

项目总结/摘要 在研究不同肿瘤类型的PI 3激酶亚型依赖性时，我们做出了非常令人惊讶的结果。 这一发现现在被证明具有相当大的临床意义。这一调查结果构成了本内审报告的基础 应用程序.我们发现，由PTEN肿瘤抑制因子缺失驱动的肿瘤是独特的， 依赖于PI 3激酶的p110β亚型。这一发现可能解释了为什么PI 3 K抑制剂首先在 PTEN无效肿瘤在临床上失败，因为它们是差的p110β抑制剂。新的p110 b特异性化合物是 现在显示出临床前景。在试图理解独特的耦合分子机制时， p110β激活导致的PTEN缺失，我们已经揭示了一套分子机制，这不仅解释了 p110β是如何响应于PTEN的丢失而被激活的，这也表明了为什么同样的肿瘤可能很快地 对PI 3 K抑制剂部分或甚至完全耐受。值得注意的是，同样的机制清楚地表明， 其他药物靶标，其可以并且应该在PTEN无效肿瘤中与PI 3 K组合攻击。我们非常 最近的数据鉴定了2种蛋白质，它们与p110β而不是p110α独特地相互作用，形成正反馈， 在不存在PTEN的情况下的环。这些蛋白质之一是小ras家族GT3，称为Rac， 与p110β相互作用，但不与p110α相互作用。我们最近发现Rac将p110 b定位于脂筏， 被激活了因此，Rac是p110β的上游激活剂。然而，Rac家族成员是独一无二的， 它们的激活剂Rac GEF被PI 3 K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性的定义。 反馈回路然而，这留下了Rac/p110β反馈回路如何启动的问题-是什么激活了 p110β/Rac的表达。我们发现激活事件依赖于小的衔接蛋白， CRKL也是p110β特异性结合蛋白。CRKL的激活通过SRC/p130 Cas信号传导发生 这一级联反应也被PTEN缺失激活。值得注意的是，SRC信号传导使细胞对PI 3 K抑制具有抗性。 最后也是最令人兴奋的是，我们发现p110 b抑制剂与免疫检查点阻断剂协同作用。我们 已经生成的数据已经显示SRC RAC PAK（RAC的另一个下游靶标）的抑制剂 在体外，脂筏形成和免疫检查点都可以与p110 b抑制剂很好地联合收割机，并且在某些情况下， 例，体内。这笔赠款将集中在更严格的测试新的药物组合，一方面， 另一方面，进一步完善我们对PTEN缺失影响的机制理解， 更好的联合治疗。