Targeting the PI3 pathway in Gliomas with PI3 inhibitors and rational combination

胶质母细胞瘤的分子特征性改变包括EGFR的扩增和EGFR的缺失。 PTEN肿瘤抑制因子，其导致PI 3 K/Akt途径的组成性激活，并提供了 我们在本项目中专注于独特的PI 3 K抑制剂PX-866（ProIX）的理由。这种渥曼青霉素类似物 提供了三个关键的改进：1）它是生物稳定的; 2）它是一个更有效的p110-a抑制剂 3）它是一种较弱的p110-p抑制剂，因此对靶点的剂量限制大大降低 所有PI 3 K抑制剂的共同毒性。我们计划检验PI 3 K抑制剂PX- 866是一种有效的治疗胶质瘤的药物，通过临床前模型和临床早期评估， 胶质母细胞瘤的临床试验然而，作为单一的信号转导抑制剂使用的有限成功 药物，这是最有可能由于代偿或侧支途径，是一个强有力的理由，探索 联合治疗根据目前对以下方面的了解，可以建议一些组合： 信号通路，我们建议在我们的模型和临床中测试最引人注目的。在同一 当我们计划确定额外的分子靶点或途径时，一旦它们被阻断， 基于siRNA合成致死性筛选，另一种药物赋予PI 3 K抑制剂协同作用。一起 这些努力将检验基于PI 3 K抑制剂的联合治疗是 有效治疗神经胶质瘤。我们的具体目标是：1）研究PX-866及其合理组合 在改进的神经胶质瘤临床前培养和动物模型中，使用 保留母体肿瘤和脑癌干细胞的分子标志。理性 组合包括PX-866和小分子药物特罗凯、索拉非尼和雷帕霉素/RAD 001， 以及治疗标准-放疗和替莫唑胺; 2）启动PX-866的临床试验，并合理 基于目标1中获得的数据，确定用于合理组合的新的协同靶标;以及3）确定用于合理组合的新的协同靶标。 使用siRNA合成致死性筛选与PX-866的药物组合。通过实现这些目标，我们将 与此同时，寻求一种有前途的PI 3 K抑制剂的临床部署和开发 合理的（目标1）和新发现的（目标3）联合靶点/疗法 将被开发，允许近期和中期联合治疗遵循个人领导 化合物（目标2）进行临床评价。因此，本项目强调的是 我们的信号转导研究计划，希望加速有前途的新治疗， 床边

Molecular alterations characteristic of glioblastoma include the amplification of EGFR and the loss of the PTEN tumor suppressor, which lead to the constitutive activation of the PI3K/Akt pathway and provides the rationale for our focus in this Project on a unique PI3K inhibitor, PX-866 (ProIX). This wortmannin analog offers three key improvements: 1) it is biologically stable; 2) it is a more potent inhibitor of the p110-a subunit of PI3K and 3) it is a weaker inhibitor of p110-p, and so shows much reduced dose limiting ontarget toxicity common to all PI3K inhibitors. We plan to test the hypothesis that the PI3K inhibitor PX- 866 is an effective therapy for glioma by evaluating it in preclinical models and in the clinic in early phase clinical trials for glioblastoma. However, the limited success of signal transduction inhibitors used as single agents, which is most likely due to compensatory or collateral pathways, is a strong rationale for exploring combination therapies. Some combinations can be suggested on the basis of current knowledge of signaling pathways, and we propose to test the most compelling in our models and the clinic. At the same time we plan to identify additional molecular target(s) or pathway(s) that would, once they are blocked by another drug, confer synergy to a PI3K inhibitor, based on siRNA synthetic lethality screening. Together these efforts will test the hypothesis that combination therapies based on PI3K inhibitors are effective in the treatment of glioma. Our Specific Aims are 1) To study PX-866 and rational combinations in improved preclinical culture and animal models of glioma, using xenografts of human glioma cells that retain the molecular hallmarks of the parental tumors and on brain cancer stem cells. Rational combinations include PX-866 and the small molecule drugs Tarceva, Sorafenib and rapamycin/RADOOl as well as the standard of care - radiation and temozolomide; 2) To initiate clinical trials of PX-866 and rational combinations, based on the data obtained in Aim 1; and 3) To identify novel synergistic targets for rational drug combinations with PX-866 using siRNA synthetic lethality screening. By completing these Aims we will pursue, in parallel, the clinical deployment of a promising PI3K inhibitor and the development of combination therapies based on it. Both rational (Aim 1) and newly discovered (Aim 3) co-targets/therapies will be developed, allowing both near-term and mid-term combination therapies to follow the individual lead compound (Aim 2) into clinical evaluation. Therefore this project emphasizes the translational dimension of our signal transduction research program with the hope of accelerating promising new treatment to the bedside.