Toward a molecular classification of human gliomas

描述（由申请人提供）：胶质母细胞瘤是人类脑肿瘤中最常见和最恶性的。最近的治疗进展改善了对原发性肿瘤的控制，其中相当一部分肿瘤对初始治疗有反应。不幸的是，所有胶质母细胞瘤都会复发并导致患者死亡。出于这个原因，目前的建议集中在复发性胶质母细胞瘤的关键问题上，研究从生物标志物的产生和评价，到了解治疗耐药的机制，再到探索新的治疗化合物。在过去的15年里，该基金支持的研究已经阐明了胶质母细胞瘤和其他恶性胶质瘤的分子遗传学基础，并表明这些肿瘤的治疗可以通过分子标记物指导;特别是，现在广泛的临床使用1 p/19 q测试在少突胶质细胞瘤中出现了根据该基金进行的研究。在上一个资助期收集的初步数据显示：胶质母细胞瘤通过与MSH 6失活相关的机制对用于治疗所有胶质母细胞瘤的烷化剂替莫唑胺（TMZ）的作用产生耐药性; MSH 6缺陷型胶质母细胞瘤在TMZ治疗期间生长更快;存在体外资源来评估TMZ诱导的DNA损伤反应和治疗抗性的缺陷。为了解决这一关键问题，我们提出了三个具体目标：1）确定胶质母细胞瘤中TMZ治疗后出现的DNA修复缺陷谱，并产生将这些事件与临床结果相关联的相关生物标志物; 2）确定DNA损伤反应缺陷导致治疗抗性的机制;和3）定义可以靶向克服由于DNA损伤反应缺陷而产生的治疗耐药性的途径。因此，所提出的方法将我们先前的临床相关生物标志物工作扩展到复发性胶质母细胞瘤的特别棘手的问题，这种肿瘤混淆了当前的治疗尝试。重要的是，通过在过去三个资助周期中继续开展这项资助支持的工作，我们的目标是产生生物标志物并阐明治疗耐药性的机制，这些机制可以在短期内转化为当前诊断和治疗方法的变化，并在长期内发展新的靶向疗法。公共卫生相关性：本提案中概述的工作的目的是研究在当前胶质母细胞瘤治疗期间选择的MSH 6和相关基因/基因产物的缺陷，以及这些缺陷如何导致治疗抗性和最终患者死亡。我们的目标是产生生物标志物并阐明治疗耐药性的机制，这些机制可以在短期内转化为当前诊断和治疗方法的变化，并在长期内转化为新型靶向治疗的发展。

DESCRIPTION (provided by applicant): Glioblastoma is the most common and most malignant of human brain tumors. Recent therapeutic advances have improved control of primary tumors, with a significant fraction of tumors responding to initial therapies. Unfortunately, all glioblastomas recur and lead to patient death. For this reason, the present proposal focuses on the crucial issue of recurrent glioblastoma-with studies extending from biomarker generation and evaluation, to understanding mechanisms of therapeutic resistance, to exploration of novel therapeutic compounds. Over the past 15 years, studies supported by this grant have clarified the molecular genetic basis of glioblastomas and other malignant gliomas and have shown that the treatment of such tumors can be guided by molecular markers; in particular, the now widespread clinical use of 1p/19q testing in oligodendrogliomas emerged from studies performed under this grant. Preliminary data gathered during the last funding period have shown: glioblastomas become resistant to the effects of the alkylating agent used to treat all glioblastomas, temozolomide (TMZ), through a mechanism associated with inactivation of MSH6; MSH6-deficient glioblastomas grow more rapidly during TMZ therapy; and in vitro resources exist to evaluate defects in the TMZ-induced DNA damage response and therapeutic resistance. To address this critical issue, we propose three Specific Aims: 1) To define the spectrum of DNA repair defects that arise after TMZ therapy in glioblastoma, and to generate relevant biomarkers relating these events to clinical outcome; 2) To define the mechanism whereby deficiencies in DNA damage responses enable therapeutic resistance; and 3) To define pathways that could be targeted to overcome therapeutic resistance due to defects in DNA damage response. The proposed approach will therefore extend our prior clinically relevant biomarker work to the particularly vexing problem of recurrent glioblastoma, a tumor that confounds current treatment attempts. Importantly, through continuing the work supported by this grant over the past three funding cycles, we aim to generate biomarkers and elucidate mechanisms of therapeutic resistance that could translate in the short term to changes in current diagnostic and therapeutic approaches and, in the long term, to the development of novel targeted therapies. PUBLIC HEALTH RELEVANCE: The purpose of the work outlined in this proposal is to investigate defects in MSH6 and related genes/gene products that are selected for during current glioblastoma therapy and how these defects lead to therapeutic resistance and eventual patient death. We aim to generate biomarkers and elucidate mechanisms of therapeutic resistance that could translate in the short term to changes in current diagnostic and therapeutic approaches and, in the long term, to the development of novel targeted therapies.