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）：靶向疗法的成功临床评估取决于未侵入性成像方法的发展，以表征早期血管和细胞在治疗后原位变化。在此应用中，我们建议使用磁共振成像（MRI）在体内进行非侵入性监测血管靶向治疗的影响，其总体目的是识别和验证预测治疗结果的早期成像生物标志物。在用肿瘤血管破坏剂（肿瘤-VDA），5,6-二甲基二甲基四乙酮-4-乙酮-4-乙酸酸（DMXAA）治疗后，将使用原发性患者肿瘤衍生的鳞状细胞癌（SCCHN）的原发性肿瘤衍生的异种移植（SCCHN）进行研究。三种MRI方法，（i）T1加权动态对比增强MRI（DCE-MRI），（ii）T2*加权的内在敏感性MRI和（III）扩散 - 加权MRI（DW-MRI）将用于测量SCCHN患者Tumor Xenograpts tumor Xenograpts to vda vda vda vda vda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功效的指标。为了检验这一假设，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之间的相关性与治疗结果。合适的算法和统计模型将用于评估成像参数和潜在的分子机制之间的关联，并允许检测可预测治疗功效的响应变量。一旦开发，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成像生物标志物，无论疾病部位如何，都可以在癌症患者的将来的临床试验中应用。理解治疗后这些组织特异性变化将有助于优化和临床应用血管靶向疗法。具体目的是：目标1。使用MRI AIM 2监测对VDA化学疗法的血管和细胞反应。评估成像数据与潜在的分子机制之间的关联目标3。识别和验证成像标记的能力预测结果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）非侵入性地监测体内血管靶向疗法的影响，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进行系统和严格的统计评估以及单个成像参数与基本机制的关联。我们设想成功识别和验证MRI反应生物标志物，这些标志物可能可能应用于以后的临床试验。