Signal Transduction Pathways in Glioblastoma

描述（申请人提供）：胶质母细胞瘤是成人最常见的恶性脑肿瘤，是所有癌症中最致命的肿瘤之一。PI3K/Akt通路信号通路的失调在胶质母细胞瘤中很常见，而PI3K/Akt通路在临床前模型中促进恶性转化、肿瘤进展和放射耐药。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PI3K信号通路失调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PI3K信号通路特异性抑制剂的可用性。该提案汇集了NCI赞助的多机构合作小组，放射治疗肿瘤小组（RTOG）的强大资源，其精心表征的临床样本，以及一组已经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人员。本提案是这些研究的重要延伸，它充分利用了nci赞助的这一重要资源。该提议的具体目的是：目的1：我们将确定PI3K通路的激活是否与胶质母细胞瘤患者生存率降低相关。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放射耐药相关。目标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反应的分子特征，以优化给药方式，并确定将从这些生物治疗药物中获益最大的患者。

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.