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

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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.