Exploiting the P13 Kinase Pathway in Human Glioma Therapy

诊断为多形性胶质母细胞瘤（GBM）的患者的治疗选择仍然令人沮丧，尽管 在了解导致这种疾病的遗传病变方面取得的进展。近年来，毒品 已经开发了针对GBM中常见的遗传改变的药物。例如，表皮 生长因子受体（EGFR）在所有GBM的三分之一到一半中扩增和过表达。然而，在这方面， EGFR抑制剂不能抑制所有EGFR过表达肿瘤的生长，这表明 另外的遗传或生物化学改变在确定对这些试剂的反应中是重要的。我们 先前的研究表明，磷酸肌醇3-激酶途径的活性在决定 GBM对这些药物有反应-在这种途径高的肿瘤中，没有患者对EGFR有反应 抑制剂，这一发现已被独立证实。因此，我们正在启动第二阶段试验， 一种EGFR抑制剂（厄洛替尼），用于复发性GBM患者，仅限于PI 3激酶水平低的患者 在切除的肿瘤中的信号传导。我们还将进一步完善我们前瞻性检测肿瘤的能力， 最有可能通过在小鼠中使用人GBM异种移植物对EGFR抑制剂应答。使用小鼠模型， 我们还将能够测试PI 3激酶信号传导的哪些成分在 确定对EGFR抑制剂的反应。在最初的融资期间，我们证明了低等级 神经胶质瘤在PTEN启动子处显示高的甲基化发生率。PTEN是一种肿瘤抑制因子， 通常拮抗PI 3-激酶活性，并且在原发性GBM中经常突变，但在继发性GBM中不突变 肿瘤的我们还发现，PTEN甲基化在继发性GBM肿瘤中非常常见，提示 PI 3-激酶途径在原发性和继发性GBM中都很重要， PTEN定义了一个独特的途径，定义了低级别到高级别的进展。因此我们建议 使用PI 3激酶通路抑制剂雷帕霉素治疗复发性、进展性、低级别胶质瘤。 最后，我们还将评估新的PI 3-激酶抑制剂的活性，该抑制剂最近由美国国家癌症研究所开发。 制药行业，并评估特定的分子特征应如何指导靶向药物的选择 治疗特定的神经胶质瘤这些新的药剂作为单一药剂显示出有希望的活性，并且在 与分子靶向治疗剂和常规细胞毒性治疗组合。

Therapeutic options for patients diagnosed with glioblastoma multiforme (GBM) remain discouraging, despite the progress made in understanding the genetic lesions that cause this disease. In the last few years, drugs have been developed that target genetic alterations frequently found in GBMs. For example, the epidermal growth factor receptor (EGFR) is amplified and overexpressed in one third to one half of all GBMs. However, inhibitors of EGFR do not inhibit the growth of all tumors with EGFR overexpression, suggesting that additional genetic or biochemical alterations are important in determining response to these agents. We previously showed that activity of the phosphoinositide 3-kinase pathway is critical in determining the ability of GBMs to respond to these drugs - in tumors in which this pathway is high, no patient responded to EGFR inhibitors, a finding that has been independently corroborated. We are therefore initiating a phase 2 trial of an EGFR inhibitor (erlotinib) in recurrent GBM patients restricted to those that display low PI3-kinase signaling in the resected tumor. We will also further refine our ability to prospectively detect tumors that are most likely to respond to EGFR inhibitors by using human GBM xenografts in mice. Using a mouse model, we will also be able to test what components of PI3-kinase signaling appear to be most important in determining response to EGFR inhibitors. In the initial funding period, we demonstrated that low-grade gliomas show a high incidence of methylation at the PTEN promoter. PTEN is a tumor supressor that normally antagonizes PI3-kinase activity, and is frequently mutated in primary, but not secondary GBM tumors. We also showed that PTEN methylation was very frequent in secondary GBM tumors, suggesting that the PI3-kinase pathway is important in both primary and secondary GBMs, and that methylation of PTEN defines a distinct pathway that defines the low-grade to high-grade progression. We therefore propose to use an inhibitor of the PI3-kinase pathway, rapamycin, in recurrent, progressive, low-grade gliomas. Finally, we will also evaluate the activity of new PI3-kinase inhibitors, recently developed by the pharmaceutical industry, and assess how specific molecular features should guide the choice of targeted therapy for a particular glioma. These novel agents display promising activity as single agents, and in combination with both molecularly targeted therapeutics and conventional cytotoxic therapy.