Targeting the PI3K Signaling Axis

磷脂酰肌醇 3 激酶 (P13K) 信号轴在大多数成人高级别细胞中被异常激活。 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肿瘤抑制基因突变； 2) EGF受体功能突变的扩增/获得 或PDGF； 3) 激活编码 pi 10a（PI3K 催化亚基）的 PI​​KSCA 基因中的突变，或者； 4） 编码 P13K 调节亚基之一 p85a 的基因 PIK3R1 发生突变。 P13K 数量 抑制剂正处于临床试验的早期阶段。其中之一是 BKM 120，由诺华和 已被证明可以穿过血脑屏障，使其成为胶质母细胞瘤的绝佳候选者 治疗。项目 2 将集中于对复发性胶质母细胞瘤患者进行 BKM 试验。广泛的目标 项目 2 的目的是使用 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 激酶的重要未解决问题 抑制剂作为胶质母细胞瘤治疗剂。除了有关基因修饰剂影响的关键数据外 来自人体试验、细胞培养和动物研究的对 BKM120（如果有）的反应将解决 使用 BKM 120 联合治疗的优化及其潜在益处 标准护理以及一些合理的靶向治疗。终于看到了伟大的希望 与针对 PI3K 单一催化亚型的抑制剂。准备此类新药物的临床测试 抑制剂，将进行临床前实验以确定个体的相对重要性 Pten 缺失导致的疾病中的 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.