Targeting the PI3K Signaling Axis

磷脂酰肌醇3激酶(P13K)信号轴在大多数成人高血压病患者中异常激活 神经胶质瘤。胶质母细胞瘤(GBM)的激活通过以下四种机制之一发生：1)功能丧失 PTEN抑癌基因的突变；2)EGF受体功能突变的扩增/获得 或PDGF；3)激活编码PI10a的PIKSCA基因突变，pI10a是PI3K的催化亚单位；或4) 编码P13K调节亚基之一p85a的基因PIK3R1突变。多个P13K 抑制剂正处于临床试验的早期阶段。其中一种，BKM 120，正在由诺华公司和 已经被证明可以通过血脑屏障，使其成为治疗胶质母细胞瘤的极佳候选细胞 心理治疗。项目2将集中在复发性胶质母细胞瘤患者的BKM试验上。总的目标是 项目2的目的是使用我们的BKM 120试验中患者的数据和临床材料-与 基因定义的小鼠模型-解决涉及PI3激酶的重要悬而未决的问题 作为胶质母细胞瘤治疗药物的抑制剂。除了关于遗传修饰剂对 对人体试验、细胞培养和动物研究的BKM120(如果有的话)的反应将解决 BKM 120与BKM 120联合使用的联合疗法的优化及其潜在好处 标准的护理，以及一些合理的针对性治疗。最后，我们看到了巨大的希望。 以PI3K的单一催化异构体为靶点的抑制剂。准备这一新类别的临床测试 抑制剂，将进行临床前试验，以确定个体的相对重要性 Pten缺失所致疾病中的P13K亚型。

The phosphatidylinositol 3 kinase (P13K) signaling axis is aberrantly activated in the majority of adult highgrade gliomas. Activation in glioblastoma (GBM) occurs via one of four mechanisms: 1) Loss of function mutations in the PTEN tumor suppressor; 2) Amplification/gain of function mutations in the receptors for EGF or PDGF; 3) Activating mutations in the PIKSCA gene that encodes pi 10a, a catalytic subunit of PI3K, or; 4) mutations in the gene PIK3R1 that encodes one ofthe P13K regulatory subunits, p85a. A number of P13K inhibitors are in the early stages of clinical trials. One of these, BKM 120, is being developed by Novartis and has been shown to pass through the blood brain barrier, making it an excellent candidate for glioblastoma therapy. Project 2 will be centered on a trial of BKM in patients with recurrent glioblastoma. The broad goal of Project 2 is to use the data and clinical materials from patients on our BKM 120 trial- in concert with genetically defined mouse models - to address important unresolved questions involving PI3 kinase inhibitors as glioblastoma therapeutics. In addition to the key data on the impact of genetic modifiers on response to BKM120 (if any) coming from the human trial, cell culture and animal studies will address optimization of, and the potential benefits from, combination therapies using BKM 120 in concert with standard of care, as well as a number of rationally targeted therapies. Finally, great promise has been seen with inhibitors targeting a single catalytic isoform of PI3K. To prepare clinical testing of this new class of inhibitors, preclinical experiments will be carried out determining the relative importance ofthe individual P13K isoforms in disease driven by Pten loss.