TOWARDS A REFINED MOLECULAR RECURSIVE PARTITIONING ANALYSIS MODEL FOR GLIOBLASTOM

描述（由申请人提供）：胶质母细胞瘤（GBMs）仍然是所有已知的人类肿瘤中最具破坏性的肿瘤之一，从最初诊断起的中位生存时间约为12-15个月。替莫唑胺化疗的引入，当与放疗同时使用并辅助使用时，已被证明可显着改善中位生存时间并增加长期GBM幸存者的百分比。肿瘤学放射治疗组（RTOG）是肿瘤学领域最大和最成熟的合作组之一，已经开发了恶性胶质瘤患者的递归划分分析（RPA）模型，主要使用临床和人口统计学变量将恶性胶质瘤患者分层为六个不同的预后分类组之一。RTOG RPA一直被认为是GBM患者预后的国际“金标准”。然而，由于最初的RTOG RPA是在20世纪90年代开发的，已经发生了两个主要的发展。首先，对GBM病理生理和观察到的治疗耐药性的分子、遗传和表观遗传机制的理解取得了快速进展，单个机构和有限的合作小组数据表明，这些生物标志物的一个子集可以作为GBM的有用预后标志物。其次，GBMs的辅助治疗模式已经从单纯放疗（当最初的RTOG RPA模型被开发时）转变为放疗联合并发和辅助替莫唑胺。因此，考虑到这两种范式的转变，改进和/或重新开发沿着这些路线更新的RTOG RPA模型变得至关重要。我们的假设是，纳入这些有希望的生物标志物将有助于显著完善现有的RTOG RPA分类模型，基于分子和临床变量的组合，建立TMZ时代治疗的GBM患者的不同预后组。修订后的RTOG RPA可以普遍用于确定未来临床试验中患者的资格，并为GBM患者基于分子的靶向治疗的未来方向提供指导。修订后的RTOG RPA模型可用于为各种GBM预后组建立“金标准”预期结果，并与涉及研究性治疗的临床试验结果进行比较，就像十年前的RTOG RPA前身模型一样。因此，这一提议的努力对这一患者群体具有极其重要和相关性，并将在国际脑肿瘤界得到普遍应用。

DESCRIPTION (provided by applicant): Glioblastomas (GBMs) remain among the most devastating of all known human tumors, with median survival times remaining around 12-15 months from initial diagnosis. The introduction of temozolomide chemotherapy, when used concurrently and adjuvantly with radiation, has been shown to significantly improve median survival times and increase the percentage of longer-term GBM survivors. The Radiation Therapy Oncology Group (RTOG), which is one of the largest and most established cooperative groups in oncology, has developed a recursive partitioning analysis (RPA) model for malignant glioma patients, using primarily clinical and demographic variables to stratify malignant glioma patients into one of six distinct prognostic classification groups. The RTOG RPA has long been considered the international "gold standard" as a prognostic model for GBM patients. However, since the original RTOG RPA was developed in the 1990's, two major developments have transpired. First, there has been a rapid advancement in the understanding of the molecular, genetic, and epigenetic mechanisms underlying the pathophysiology and the observed treatment resistance of GBMs, with single institution and limited cooperative group data suggesting that a subset of these biomarkers could serve as useful prognostic markers in GBM. Second, there has been a shift in the adjuvant treatment paradigm of GBMs away from radiation alone (when the original RTOG RPA model was developed) to radiation combined with concurrent and adjuvant temozolomide. Therefore, given these two paradigm shifts, it becomes essential to refine and/or redevelop an RTOG RPA model that is updated along these lines. It is our hypothesis that inclusion of these promising biomarkers will serve to significantly refine the existing RTOG RPA classification model to establish distinct prognostic groups of GBM patients treated in the TMZ era, based on a combination of molecular and clinical variables. The revised RTOG RPA resulting from the proposed effort may be universally used to determine patient eligibility in future clinical trials, as well as to provide guidance with regards to future directions for molecularly-based targeted therapies for GBM patients. The revised RTOG RPA model can be used to establish the "gold standard" expected outcomes for various the prognostic groups of GBM against which the results from clinical trials involving investigational therapies can be compared, much like its decade's old RTOG RPA predecessor model. Therefore, this proposed endeavor is of the utmost importance and relevance for this patient population and will be universally utilized in the international brain tumor community. With regards to methodology, this proposal represents a joint effort between the RTOG and the laboratories of Arnab Chakravarti, MD, Chair and Professor of Radiation Oncology at the Arthur G. James Comprehensive Cancer Center of the Ohio State University and Kenneth Aldape, MD, Professor of Neuropathology at the MD Anderson Cancer Center. Drs. Chakravarti and Aldape are Chair and Co-Chair of the RTOG Brain Tumor Translational Research Group, respectively. Our strategy will be to utilize biorepository specimens from the recently completed RTOG 0525 to accomplish our stated objectives. RTOG 0525 was a Phase III Study conducted in North America, Europe, and Asia comparing dose-dense versus standard dose TMZ when combined with radiation for newly-diagnosed GBM. Tissue blocks were prospectively collected on each and every one of the 1173 GBM patients enrolled on this RTOG study, which have been made available for our NIH challenge grant effort. We will revise the existing RTOG RPA classification model to include not only clinical/demographic variables, but also key molecular, genetic, and epigenetic variables. To this end, we shall validate key signal transduction biomarkers, genetic, and epigenetic markers that have been previously shown to be of prognostic value in smaller GBM studies by our group and others. This data will be combined with the clinical and demographic data previously found to be of importance in the previous RTOG RPA model to generate a revised RPA classification model pertinent to TMZ-treated GBM patients and one that is refined to include molecular, genetic, and epigenetic data of significance.