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

胶质母细胞瘤的分子改变特征包括EGFR的扩增和EGFR的缺失 PTEN肿瘤抑制因子，导致PI3K/Akt通路的结构性激活，并提供 我们将重点放在一种独特的PI3K抑制剂PX-866(ProIX)上的理由。这个Wortmannin模拟 提供了三个关键的改进：1)生物稳定性；2)它是p110-a的更有效的抑制剂 PI3K的亚基和3)它是p110-p的较弱的抑制剂，因此对靶的剂量限制大大降低 所有PI3K抑制剂的共同毒性。我们计划测试PI3K抑制剂Px- 通过临床前模型和早期临床评估，866是一种治疗胶质瘤的有效方法。 胶质母细胞瘤的临床试验。然而，信号转导抑制剂作为单一药物使用的成功有限 代理人，这很可能是由于补偿或侧支途径，是一个强有力的理由来探索 综合疗法。根据当前的知识，可以提出一些组合 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。同时 我们计划确定额外的分子靶点(S)或途径(S)，一旦它们被 另一种药物，基于siRNA合成致死性筛选，赋予PI3K抑制剂协同作用。同舟共济 这些努力将检验基于PI3K抑制剂的联合疗法是 对治疗神经胶质瘤有效。我们的具体目标是：1)研究PX-866和有理组合 在改进的胶质瘤临床前培养和动物模型中，使用人脑胶质瘤细胞的异种移植 保留亲代肿瘤和脑癌干细胞的分子特征。理性 联合药物包括PX-866和小分子药物Tarceva、Sorafenib和雷帕霉素/RADO1AS 以及护理放射和替莫唑胺的标准；2)启动PX-866和Rational的临床试验 根据目标1中获得的数据进行组合；以及3)为Rational确定新的协同目标 使用siRNA合成致死性筛选的药物与PX-866的组合。通过实现这些目标，我们将 同时，寻求一种有前途的PI3K抑制剂的临床部署和开发 以此为基础的综合疗法。Rational(目标1)和新发现的(目标3)共同靶点/疗法 将被开发，允许近期和中期联合疗法跟随个人领导 复方(目标2)纳入临床评价。因此，这个项目强调翻译的维度 我们的信号转导研究计划，希望加速有希望的新疗法 在床边。

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.