DEVELOPMENT AND VALIDATION OF AN IMAGING-BASED BIOMARKER OF THERAPEUTIC EFFICACY

描述(申请人提供)：靶向治疗的成功临床评估依赖于非侵入性成像方法的发展，以表征治疗后早期血管和细胞的原位变化。在这一应用中，我们建议使用磁共振成像(MRI)在体内非侵入性地监测血管靶向治疗的效果，总体目标是识别和验证预测治疗结果的早期成像生物标记物。研究将使用原发患者头颈部鳞状细胞癌(SCCHN)肿瘤来源的异种移植，在接受肿瘤血管干扰剂(Tumor-VDA)、5，6-二甲基黄原酮-4-乙酸(DMXAA)单独治疗并与化疗药物伊立替康联合治疗后进行。我们将使用三种MRI方法，(I)T1加权动态对比增强MRI(DCE-MRI)，(Ii)T2*加权固有敏感性MRI，(Iii)扩散加权MRI(DW-MRI)来测量SCCHN患者肿瘤移植瘤对VDA化疗的血管和细胞反应。我们的假设是，在治疗后不久获得的这些MRI参数的量化变化将作为治疗效果的指标。为了验证这一假设，我们将使用临床适用的终点进行系统和严格的统计分析，以检测成像和非成像变量与治疗结果之间的相关性。适当的算法和统计模型将被用来评估成像参数和潜在的分子机制之间的关联，并允许检测预测治疗效果的反应变量。一旦开发完成，我们将使用相同的治疗条件在单独的队列中前瞻性地验证预测算法。基于我们令人鼓舞的初步结果，我们设想成功识别和验证一种成像生物标记物，该标记物可以应用于未来癌症患者的临床试验，而不考虑疾病的部位。了解治疗后这些组织特异性的变化将有助于血管靶向治疗的优化和临床应用。具体目标是：目标1.使用MRI Aim监测血管和细胞对VDA化疗的反应2.评估影像数据与潜在分子机制之间的联系目标3.识别和验证影像标记物预测结果的能力 公共卫生相关性：这项提案的总体重点是使用磁共振成像(MRI)在体内非侵入性地监测血管靶向治疗的效果，目的是识别和验证治疗结果的早期成像生物标志物。利用原发患者的肿瘤异种移植，我们计划对MRI生物标记物的预测能力以及个体成像参数与潜在机制的关联进行系统和严格的统计评估。我们设想成功地识别和验证一种MRI反应生物标记物，该标记物可能在未来的临床试验中应用。

DESCRIPTION (provided by applicant): Successful clinical evaluation of targeted therapies is dependent on the development of noninvasive imaging methods to characterize early vascular and cellular changes in situ following treatment. In this application, we propose to non-invasively monitor the effects of vascular-targeted therapy in vivo using magnetic resonance imaging (MRI) with the overall goal of identifying and validating early imaging biomarkers that are predictive of treatment outcome. Studies will be carried out using primary patient tumor-derived xenografts of squamous cell carcinomas of the head and neck (SCCHN) following treatment with a tumor vascular disrupting agent (tumor-VDA), 5,6-dimethylxanthenone-4-acetic acid (DMXAA) alone and in combination with the chemotherapeutic agent, Irinotecan. Three MRI methods, (i) T1-weighted dynamic contrast-enhanced MRI (DCE-MRI), (ii) T2*weighted intrinsic susceptibility MRI, and (iii) diffusion-weighted MRI (DW-MRI) will be employed to measure the vascular and cellular response of SCCHN patient tumor xenografts to VDA chemotherapy. It is our hypothesis that quantitative changes in these MRI parameters obtained shortly after treatment will serve as indicators of therapeutic efficacy. To test this hypothesis, we will carry out systematic and rigorous statistical analyses powered to detect correlation between imaging and non-imaging variables with treatment outcome using clinically applicable end points. Suitable algorithms and statistical models will be used to evaluate the association between imaging parameters and underlying molecular mechanisms and to allow detection of response variables that are predictive of therapeutic efficacy. Once developed, we will prospectively validate the prediction algorithm in a separate cohort using the same treatment conditions. Based on our encouraging preliminary results, we envision successful identification and validation of an imaging biomarker that could be applied in future clinical trials in cancer patients irrespective of the disease site. Understanding these tissue-specific changes following treatment would assist in the optimization and clinical application of vascular-targeted therapies. The specific aims are: Aim 1. To monitor vascular and cellular response to VDA chemotherapy using MRI Aim 2. To evaluate the association between imaging data and underlying molecular mechanisms Aim 3. To identify and validate the ability of imaging markers to predict outcome PUBLIC HEALTH RELEVANCE: The overall focus of this proposal is to non-invasively monitor the effects of vascular-targeted therapy in vivo using magnetic resonance imaging (MRI) with the goal of identifying and validating early imaging biomarkers of treatment outcome. Using primary patient tumor xenografts, we plan to carry out a systematic and rigorous statistical evaluation into the predictive ability of MRI biomarkers along with association of individual imaging parameters to underlying mechanisms. We envision successful identification and validation of an MRI response biomarker that could potentially be applied in future clinical trials.