TOWARDS A REFINED MOLECULAR RECURSIVE PARTITIONING ANALYSIS MODEL FOR GLIOBLASTOM

描述(申请人提供)：胶质母细胞瘤(GBM)仍然是所有已知人类肿瘤中最具破坏性的，从最初诊断到中位生存期仍在12-15个月左右。研究表明，替莫唑胺化疗与放射治疗同时进行时，可显著延长中位生存期，并增加长期GBM存活者的百分比。放射治疗肿瘤学小组(RTOG)是肿瘤学领域最大和最成熟的合作小组之一，它为恶性胶质瘤患者开发了一个递归分割分析(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成六个不同的预后分类组之一。RTOG RPA长期以来一直被认为是判断GBM患者预后的国际“黄金标准”。然而，自从最初的RTOG RPA在20世纪90年代的S开发以来，出现了两个主要的发展。首先，对GBM病理生理学和观察到的治疗耐药的分子、遗传和表观遗传学机制的理解有了迅速的进展，单一机构和有限的合作小组数据表明，这些生物标记物的子集可以作为GBM有用的预后标记物。其次，GBM的辅助治疗模式已经从单纯的放射治疗(最初的RTOG RPA模型开发时)转变为联合放射治疗和同时辅助替莫唑胺。因此，考虑到这两种范式转变，精炼和/或重新开发按照这些思路进行更新的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改进现有的RTOG RPA分类模型，以建立基于分子和临床变量的组合，在TMZ时代治疗的GBM患者的不同预后分组。修订后的RTOG RPA可能被普遍用于在未来的临床试验中确定患者的资格，以及为GBM患者的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GBM的各种预后组建立“金标准”预期结果，与涉及研究疗法的临床试验的结果进行比较，就像其十年前的RTOG RPA前身模型一样。因此，这项拟议的努力对这一患者群体具有极其重要和相关的意义，并将在国际脑肿瘤社区得到普遍应用。 在方法方面，这项建议是RTOG和Arnab Chakravarti(俄亥俄州立大学Arthur G.James综合癌症中心放射肿瘤学主席兼教授)和Kenneth Aldape(MD安德森癌症中心神经病理学教授)的实验室共同努力的结果。查克拉瓦蒂博士和阿尔达普博士分别担任RTOG脑瘤翻译研究组主席和联席主席。我们的战略将是利用最近完成的RTOG 0525的生物储存库样本来实现我们所宣布的目标。RTOG 0525是在北美、欧洲和亚洲进行的一项第三阶段研究，比较了剂量密度与标准剂量TMZ在结合放射治疗新诊断的GBM时的差异。组织块前瞻性地收集了参加这项RTOG研究的1173名GBM患者的每一个人的组织块，这些组织块已经提供给我们的NIH挑战拨款努力。我们将修订现有的RTOG RPA分类模型，不仅包括临床/人口学变量，还包括关键的分子、遗传和表观遗传学变量。为此，我们将验证关键的信号转导生物标记物、遗传和表观遗传学标记物，这些标记物以前已经被我们小组和其他人证明在较小的GBM研究中具有预后价值。这些数据将与以前的RTOG RPA模型中发现的重要的临床和人口学数据相结合，以生成与TMZ治疗的GBM患者相关的修订的RPA分类模型，该模型经过改进以包括有意义的分子、遗传和表观遗传学数据。

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.