Targeting the PI3K Signaling Axis

磷脂酰肌醇3激酶（P13 K）信号转导轴在大多数成年高分化的乳腺癌中异常激活。 神经胶质瘤胶质母细胞瘤（GBM）中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 3）编码P110 a（PI 3 K的催化亚基）的PIKSCA基因中的激活突变，或; 4） 编码P13 K调节亚基之一p85 a的基因PIK 3R 1突变。一批P13 K 这些抑制剂还处于临床试验的早期阶段。其中之一，BKM 120，正在开发的诺华和 已被证明可以通过血脑屏障，使其成为胶质母细胞瘤的绝佳候选者 疗法项目2将集中于BKM在复发性胶质母细胞瘤患者中的试验。广泛的目标 项目2的第一步是使用我们BKM 120试验患者的数据和临床材料-与 基因定义的小鼠模型-解决涉及PI 3激酶的重要未解决问题 抑制剂作为胶质母细胞瘤治疗剂。除了关于遗传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BKM 120的反应（如有）将解决 使用BKM 120与以下药物联合治疗的优化和潜在获益 标准治疗，以及一些合理的靶向治疗。最后， 与靶向PI 3 K的单一催化亚型的抑制剂。为了准备这类新药物的临床试验 抑制剂，将进行临床前实验，以确定个体的相对重要性， 疾病中的P13 K亚型由Pten损失驱动。

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.