Glioblastoma - Molecular Analysis for Clinical Trials

描述(申请人提供)：激酶抑制剂已经显示出治疗某些类型的癌症的巨大希望，例如白血病和一些实体肿瘤。激酶抑制剂是否会在癌症治疗中发挥更普遍的作用？胶质母细胞瘤是成人最常见的恶性原发脑瘤，也是所有癌症中最致命的一种，是解决这一问题的理想临床模型。在临床前的胶质母细胞瘤模型中，慢性PI3K/Akt通路的激活促进了恶性转化和肿瘤的进展，并且通常在胶质母细胞瘤患者的样本中检测到。然而，由于无法确定哪位患者最有可能受益，PI3K/Akt途径抑制剂的临床应用受到了严重限制。由于在形态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不同的敏感性，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出一种分析常规处理的胶质母细胞瘤患者活检组织中PI3K/Akt通路激活的方法，该方法可能被用于确定哪些患者最有可能从激酶抑制剂治疗中受益(Choe等人，2003)，我们已经成为许多正在进行的、由研究者发起的多中心靶向通路抑制剂临床试验的分子相关性分析中心。这一建议将为我们提供一个独特的机会，以确定慢性PI3K通路激活对患者生存的影响，确定PI3K通路激活是否可用于选择靶向抑制剂治疗的患者，并开发可用于在基于分子的临床试验中检测通路抑制和预测患者反应的替代分子标记。

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.