Signal Transduction Pathways in Glioblastoma

描述(申请人提供)：胶质母细胞瘤是最常见的成人恶性脑肿瘤，也是所有癌症中最致命的癌症之一。PI3K/Akt信号通路的失控在胶质母细胞瘤中很常见，PI3K/Akt信号通路在临床前模型中促进恶性转化、肿瘤进展和辐射抵抗。然而，它对胶质母细胞瘤患者生存和治疗反应的影响尚不清楚。确定去调控的PI3K信号通路对胶质母细胞瘤患者生存和治疗反应的影响可能直接转化为改善胶质母细胞瘤患者的治疗，特别是考虑到特定的PI3K信号通路特异性抑制剂的可用性。这项建议汇集了NCI发起的多机构合作小组的强大资源，放射治疗肿瘤学小组(RTOG)及其精心表征的临床样本，以及一支已证明有能力分析胶质母细胞瘤患者样本中PI3K途径激活状态的研究团队。这项建议是这些研究的重要扩展，它充分利用了NCI赞助的这一重要资源。这项建议的具体目的是：目标1：我们将确定PI3K通路的激活是否与胶质母细胞瘤患者的存活率降低有关。目的2：我们将确定PI3K通路的激活是否与胶质母细胞瘤患者的辐射抵抗有关。目的3：在正在进行和计划中的RTOG试验中，我们将确定胶质母细胞瘤对EGFR、mTOR和法尼基转移酶抑制剂的反应的分子特征，以优化给药，并确定哪些患者将从这些生物治疗药物中获得最大好处。

DESCRIPTION (provided by applicant): Glioblastoma is the most common malignant brain tumor of adults and is among the most lethal of all cancers. Deregulation of the PI3K/Akt pathway signaling, which promotes malignant transformation, tumor progression and radiation-resistance in pre-clinical models, is common in glioblastomas. However, its impact on glioblastoma patient survival and response to therapy is not known. Determining the effect of deregulated PI3K pathway signaling on glioblastoma patient survival and response to therapy may potentially translate directly into improved therapy for glioblastoma patients, particularly in light of the availability of specific PI3K signaling pathway specific inhibitors. This proposal brings together the powerful resources of an NCI sponsored multi-institutional cooperative group, the Radiation Therapy Oncology Group (RTOG), with its meticulously characterized clinical samples, and a team of investigators that has demonstrated ability to analyze the activation state of the PI3K pathway in glioblastoma patient samples. This proposal is an important extension of these studies, and it takes full advantage of this important NCI-sponsored resource. The specific aims of this proposal are: Aim 1: We will determine whether activation of the PI3K pathway is associated with diminished survival of glioblastoma patients. Aim 2: We will determine whether activation of the PI3K pathway is associated with radiation resistance in glioblastoma patients. Aim 3: We will identify molecular features of glioblastomas that underlie response to EGFR, mTOR and farnesyl transferase inhibitors under investigation in ongoing and planned RTOG trials to optimize delivery and identify patients who will derive greatest benefit from these biotherapeutic agents.