Glioblastoma - Molecular Analysis for Clinical Trials

描述（由申请人提供）：激酶抑制剂已被证明在治疗某些类型的癌症，如白血病和一些实体瘤方面具有很大的前景。激酶抑制剂在癌症治疗中是否会发挥更广泛的作用？胶质母细胞瘤是成人最常见的恶性原发性脑肿瘤，也是所有癌症中最致命的一种，代表了解决这一问题的理想临床模型。慢性PI 3 K/Akt通路活化促进临床前胶质母细胞瘤模型中的恶性转化和肿瘤进展，并且通常在胶质母细胞瘤患者样品中检测到。然而，PI 3 K/Akt通路抑制剂的临床应用由于无法确定哪种患者最有可能受益而受到严重限制。由于形态学上难以区分的胶质母细胞瘤可能具有不同类别的致癌基因/信号通路激活，这可能使它们对激酶抑制剂具有差异敏感性，因此开发检测通路激活的方法至关重要。我们的实验室已经开发了一种分析常规处理的胶质母细胞瘤患者活检中的PI 3 K/Akt途径活化的方法，其可以潜在地用于确定哪些患者最有可能受益于激酶抑制剂疗法（Choe et al.，2003年），我们已经成为一个分子相关分析中心的一些正在进行的，制药商发起的多中心临床试验的靶向途径抑制剂。该提案将为我们提供一个独特的机会，以确定慢性PI 3 K通路激活对患者生存的影响，以确定PI 3 K通路激活是否可用于选择患者进行靶向抑制剂治疗，并开发替代分子标志物，可用于检测通路抑制和预测基于分子的临床试验中患者的反应。

DESCRIPTION (provided by applicant): Kinase inhibitors have demonstrated great promise for the treatment of some types of cancer, such as leukemia and a few solid tumors. Will kinase inhibitors have a more general role in cancer therapy? Glioblastoma, the most common malignant primary brain tumor of adults and one of the most lethal of all cancers, represents an ideal clinical model to address this question. Chronic PI3K/Akt pathway activation promotes malignant transformation and tumor progression in pre-clinical glioblastoma models, and is commonly detected in glioblastoma patient samples. However, clinical application of PI3K/Akt pathway inhibitors has been severely limited by an inability to determine which patient is most likely to benefit. Because morphologically indistinguishable glioblastomas can have distinct classes of causal oncogene/signaling pathway activation that may render them differentially sensitive to kinase inhibitors, it is crucial to develop methods of detecting pathway activation. Our laboratory has developed a method of analyzing PI3K/Akt pathway activation in routinely processed glioblastoma patient biopsies, which may potentially be used to determine which patients are most likely to benefit from kinase inhibitor therapy (Choe et al., 2003), and we have become a molecular correlates analysis center for a number of ongoing, investigator-initiated multi-center clinical trials of targeted pathway inhibitors. This proposal will provide us with a unique opportunity to determine the impact of chronic PI3K pathway activation on patient survival, to determine whether PI3K pathway activation can be used to select patients for targeted inhibitor therapy, and to develop surrogate molecular markers that can be used to detect pathway inhibition and predict response in patients in molecularly-based clinical trials.