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

基于成像的治疗效果生物标志物的开发和验证

基本信息

批准号：
7990122
负责人：
Mukund Seshadri
金额：
$ 18.47万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-14 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7990122
关键词：
Adverse effects Aftercare Algorithms Angiogenesis Inhibitors Animal Model Animals Apoptosis Applications Grants Area Biologic Characteristic Biological Biological Assay Biological Markers Biological Models Blood Vessels Cancer Patient Cell Proliferation Cellularity Classification Clinical Clinical Trials Data Detection Development Diagnostic Diffusion Diffusion Magnetic Resonance Imaging Dimethylxanthenone Acetic Acid Disorder by Site Dose Drug Delivery Systems Evaluation Exhibits Feedback Functional Imaging Future Goals Growth Head and Neck Squamous Cell Carcinoma Head and neck structure Heterogeneity Histologic Image Immunohistochemistry In Situ Individual Interleukin-6 Ionizing radiation Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of lung Measures Mediator of activation protein Methods Modeling Molecular Molecular Biology Monitor Multivariate Analysis Mus Necrosis Neoplasms in Vascular Tissue Normal tissue morphology Operative Surgical Procedures Outcome Patient Selection Patients Permeability Pharmacodynamics Phase I Clinical Trials Phase II Clinical Trials Physiology Play Poison Positron-Emission Tomography Pre-Clinical Model Preclinical Drug Evaluation Predisposition Protocols documentation Publishing Radioactive Tracers Research Proposals Resolution Role Safety Schedule Serotonin Site Solid Neoplasm Specimen Squamous cell carcinoma Statistical Models System Techniques Testing Therapeutic Therapeutic Agents Tissues Translations Transplantation Treatment Efficacy Treatment outcome Tumor Cell Line Tumor Necrosis Factor-alpha Tumor Tissue Tumor Volume Tumor-Derived Validation Vascular Permeabilities Weight X-Ray Computed Tomography Xenograft procedure angiogenesis anticancer treatment base cancer therapy cell killing chemotherapeutic agent chemotherapy clinical application clinically relevant cohort cytotoxic density human TNF protein imaging modality in vivo interest irinotecan molecular marker neoplastic cell novel oncology patient population pre-clinical preclinical evaluation preclinical study prognostic prospective public health relevance research clinical testing research study response soft tissue standard measure success tumor tumor growth tumor xenograft validation studies

项目摘要

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.

描述（由申请人提供）：靶向治疗的成功临床评估取决于无创成像方法的开发，以表征治疗后早期血管和细胞原位变化。在此应用中，我们建议使用磁共振成像（MRI）无创地监测体内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。将使用原发患者的头颈鳞状细胞癌 (SCCHN) 肿瘤来源的异种移植物进行研究，这些移植物经过肿瘤血管破坏剂 (肿瘤-VDA)、5,6-二甲基呫吨酮-4-乙酸 (DMXAA) 治疗）单独使用或与化疗药物伊立替康联合使用。将采用三种 MRI 方法，(i) T1 加权动态对比增强 MRI (DCE-MRI)、(ii) T2* 加权内在磁化率 MRI 和 (iii) 扩散加权 MRI (DW-MRI) 来测量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。为了检验这一假设，我们将进行系统且严格的统计分析，以使用临床适用的终点来检测成像和非成像变量与治疗结果之间的相关性。合适的算法和统计模型将用于评估成像参数和潜在分子机制之间的关联，并允许检测可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志物，该标志物可以应用于未来癌症患者的临床试验，无论疾病部位如何。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 监测血管和细胞对 VDA 化疗的反应目标 2. 评估成像数据与潜在分子机制之间的关联目标 3. 识别和验证成像标志物预测结果的能力公共健康相关性：该提案的总体重点是使用磁共振成像（MRI）无创地监测体内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以及个体成像参数与潜在机制的关联进行系统且严格的统计评估。我们设想成功识别和验证 MRI 反应生物标志物，该标志物有可能应用于未来的临床试验。