Imaging and Tissue Biomarkers in Patients with Newly Diagnosed GBM

描述(申请人提供)：该项目的目标是将代谢和生理磁共振成像数据整合到新诊断的多形性胶质母细胞瘤(GBM)患者的临床治疗中，这些患者正在接受放射、化疗和抗血管生成的联合治疗。我们目前的研究已经提供了强有力的证据，表明磁共振波谱成像(MRSI)、灌注加权成像(PWI)和扩散加权成像(DWI)可以提供关于这些病变的生物学行为的信息，这些信息可能对临床决策有价值。我们建议探索这些成像方法在量化成像参数的变化和评估同时接受enzastaurin、替莫唑胺和放射疗法(ETRT)治疗的患者的疗效方面的影响。ETRT是一种结合细胞毒性和抗血管生成方法的治疗策略。第一个感兴趣的领域是验证选定的成像变量的生物学解释，这些变量被认为是肿瘤范围、异质性和治疗反应性的代表性替代指标，以及与生存相关的预后意义。第二个感兴趣的领域是评估ETRT前的影像特征及其由于ETRT而发生的短期和长期变化，以便量化和评估治疗反应。以前的研究还没有利用最先进的代谢和生理成像方法来选择患者，识别微观疾病和异质性，或者评估治疗的反应。我们认为，关键是要确定这种方法是否可行，并获得有助于决定如何最好地将这些信息整合到未来临床试验中的证据。 特殊目的1将通过免疫组织化学和体外核磁共振波谱对新诊断的GBM患者的图像引导手术样本提供特定的活体成像和组织特征之间的直接关联。这将建立体内和体外磁共振参数与分子形态所定义的生物行为之间的联系。具体目标2将分析参加机构ETRT第二阶段临床试验的患者的GBM特征。它将检查放疗前MR参数与放疗结束后6个月内多个时间点的后续影像变化之间的关系。虽然这项建议的重点是一项特定的临床试验，但所获得的知识将对选择和设计许多其他类型的抗血管生成和分子靶向治疗具有广泛的影响，并可能加强基于非侵入性成像的治疗反应解释，改变对GBM患者肿瘤负担的定义，以及改善未来临床试验的患者选择。

DESCRIPTION (provided by applicant): The objective of this project is to integrate metabolic and physiologic MR imaging data into the clinical management of patients with newly diagnosed glioblastoma multiforme (GBM) who are being treated with combined radiation, chemo and antiangiogenic therapy. Our current studies have provided strong evidence that Magnetic Resonance Spectroscopic Imaging (MRSI), Perfusion Weighted imaging (PWI) and Diffusion Weighted Imaging (DWI) produce information concerning the biological behavior of such lesions that is likely to be valuable for clinical decision making. We propose to explore the impact of these imaging methods with respect to quantifying changes in imaging parameters and assessing therapeutic response in patients treated with concurrent Enzastaurin, Temozolomide and Radiation Therapy (ETRT), a therapeutic strategy that combines cytotoxic and antiangiogenic approaches. The first area that is of interest is to validate the biological interpretation of selected imaging variables presumed to be representative surrogates for tumor extent, heterogeneity, and therapeutic responsiveness, as well as prognostic significance with respect to survival. The second area of interest is in evaluating imaging characteristics prior to ETRT and their short and longer term changes that occur as a result of ETRT in order to quantify and assess treatment response. Previous studies have not utilized state of the art metabolic and physiologic imaging methods to select patients, to identify microscopic disease and heterogeneity or to evaluate response to therapy. We believe that it is critical to determine whether this approach is feasible and to obtain evidence that would help in deciding how to best integrate such information into future clinical trials. Specific Aim 1 will provide direct correlation between specific in vivo imaging and tissue characteristics by immunohistochemical and ex vivo NMR spectroscopy of image guided surgical samples from patients with newly diagnosed GBM. This will establish the link between in vivo and ex vivo MR parameters and biological behavior as defined by molecular morphology. Specific Aim 2 will analyze the characteristics of GBM in patients who are participating in an institutional Phase II clinical trial of ETRT. It will examine the relationship between pre-ETRT MR parameters and subsequent imaging changes at multiple time points up to 6 months after completion of RT. While the focus of this proposal is on one specific clinical trial, the knowledge that will be gained has broad implications for selecting and designing many other types of antiangiogenic and molecularly targeted therapies and is likely to enhance the non-invasive imaging based interpretation of treatment response, change the definition of tumor burden in patients with GBM as well as improve patient selection for future clinical trials.