Signal Transduction Pathways in Glioblastoma

描述（由申请人提供）：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。PI 3 K/Akt通路信号传导的失调在胶质母细胞瘤中很常见，其在临床前模型中促进恶性转化、肿瘤进展和放射抗性。然而，其对胶质母细胞瘤患者生存率和治疗反应的影响尚不清楚。确定去调节的PI 3 K通路信号传导对胶质母细胞瘤患者存活和对治疗的反应的影响可能直接转化为胶质母细胞瘤患者的改善的治疗，特别是鉴于特异性PI 3 K信号传导通路特异性抑制剂的可用性。该提案汇集了NCI赞助的多机构合作组的强大资源，放射治疗肿瘤学组（RTOG），其精心表征的临床样本，以及一组研究人员，他们已经证明有能力分析胶质母细胞瘤患者样本中PI 3 K通路的激活状态。这项建议是这些研究的重要延伸，它充分利用了这一重要的NCI赞助的资源。本提案的具体目标是：目标1：我们将确定PI 3 K通路的激活是否与胶质母细胞瘤患者的生存率降低相关。目的2：我们将确定PI 3 K通路的激活是否与胶质母细胞瘤患者的放射抵抗有关。目标3：我们将确定胶质母细胞瘤的分子特征，这些分子特征是正在进行和计划进行的RTOG试验中研究的EGFR、mTOR和法尼基转移酶抑制剂的反应基础，以优化给药方式，并确定将从这些生物制剂中获得最大获益的患者。

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.