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

描述（由申请方提供）：靶向治疗的成功临床评价取决于无创成像方法的发展，以表征治疗后原位早期血管和细胞变化。在本申请中，我们提出使用磁共振成像（MRI）在体内无创监测血管靶向治疗的效果，总体目标是识别和验证可预测治疗结果的早期成像生物标志物。将使用肿瘤血管阻断剂（肿瘤-VDA）、5，6-二甲基咕吨酮-4-乙酸（DMXAA）单独治疗和与化疗药物伊立替康联合治疗后的原发性头颈部鳞状细胞癌（SCCHN）患者肿瘤源性异种移植物进行研究。将采用三种MRI方法（i）T1加权动态对比增强MRI（DCE-MRI）、（ii）T2* 加权固有磁化率MRI和（iii）弥散加权MRI（DW-MRI）测量SCCHN患者肿瘤异种移植物对VDA化疗的血管和细胞反应。我们的假设是，治疗后不久获得的这些MRI参数的定量变化将作为治疗效果的指标。为了验证这一假设，我们将进行系统和严格的统计分析，以检测成像和非成像变量与临床适用终点的治疗结果之间的相关性。将使用合适的算法和统计模型来评价成像参数与潜在分子机制之间的关联，并允许检测预测治疗功效的响应变量。一旦开发完成，我们将在使用相同治疗条件的单独队列中前瞻性验证预测算法。基于我们令人鼓舞的初步结果，我们设想成功鉴定和验证一种成像生物标志物，该生物标志物可应用于未来的癌症患者临床试验，而无论疾病部位如何。了解治疗后这些组织特异性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 2监测血管和细胞对VDA化疗的反应。评估影像学数据与潜在分子机制之间的关联。识别并验证影像学标记物预测结局的能力 公共卫生相关性：该提案的总体重点是使用磁共振成像（MRI）在体内无创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。使用原发性患者肿瘤异种移植物，我们计划对MRI生物标志物的预测能力沿着个体成像参数与潜在机制的关联进行系统和严格的统计学评价。我们设想成功识别和验证MRI反应生物标志物，可能应用于未来的临床试验。

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.