Development of Imaging Biomarkers for Treatment Response

项目一：在癌症死因中，脑瘤位居儿科第二位 年龄组，中年男性排名第四。恶性胶质瘤一直都是致命的；只有50% 患者从确诊之日起可存活一年。这些严峻的统计数据突显出迫切需要 早期评估这些患者的治疗效果。敏感的和早期的替代预测指标 患者的治疗结果将改善护理，并可能改善预后，因为 为每个患者提供个体化和调整治疗的机会。这个项目的中心假设是 治疗干预的有效性可以在肿瘤缩小之前用 合适的成像替代反应标记物以及用于结果预测的最佳替代指标将 依赖于治疗靶点。基因工程PDGF驱动的转基因脑胶质瘤模型的建立 将与在项目2中开发并在本项目中使用的特定分子成像记者一起使用(#1) 评估细胞毒性以及分子靶向治疗干预。对肿瘤的治疗作用 1H MR代谢物、肿瘤灌注和扩散将根据细胞毒药物(化疗、 放射和化学辐射)和分子靶向药物(PDGFR酪氨酸激酶抑制剂、Akt 抑制剂、mTOR抑制剂和MEK抑制剂)以确定用于评估的最佳替代标记物 每一类治疗的治疗反应。磁共振在检测治疗效果中的作用 对脑肿瘤的反应将在两个特定的目标上进行评估。来自肿瘤的磁共振数据将与 通过动物存活率、肿瘤体积/生长率的变化和组织学来确定疗效 哪个特定的或组合的成像-可观察参数可用作 预测治疗结果。这些研究将为配对特定成像提供理论基础 替代标记物进行治疗干预，以获得最有效的早期读数 治疗反应。这些啮齿动物影像研究将作为翻译和评估的基础 这些方法在临床上的建议，如项目#3。健康：总体而言，这项研究努力将 为联合应用分子靶向疗法开展临床试验提供理论依据 恶性脑瘤的治疗。此外，用于治疗早期评估的成像生物标记物 将确定和验证响应，这将导致患者治疗的个体化。

PROJECT 1: Among the causes of death due to cancer, brain tumors are ranked second in the pediatric age group and fourth in middle-aged men. Malignant gliomas have remained uniformly fatal; only 50% of patients survive one year from the time of diagnosis. These stark statistics underscore the urgent need for an early assessment of therapeutic efficacy in these patients. Sensitive and early surrogate predictors of therapeutic outcome for patients would improve care and potentially improve prognosis due to the opportunity to individualize and adjust the treatment to each patient. The central hypothesis of this project is that the effectiveness of therapeutic interventions can be determined prior to tumor shrinkage using appropriate imaging surrogate response markers and that the optimal surrogate for outcome prediction will be dependent upon the therapeutic target. A genetically engineered PDGF-driven transgenic glioma model will be utilized with specific molecular imaging reporters developed in Project #2 and used in this Project (#1) to evaluate cytotoxic, as well as molecularly targeted therapeutic interventions. Therapeutic effects on tumor 1H MR metabolites, tumor perfusion and diffusion will be evaluated against cytotoxic agents (chemotherapy, radiation and chemoradiation) and molecularly targeted agents (a PDGFR tyrosine kinase inhibitor, an Akt inhibitor, an mTOR inhibitor and a MEK inhibitor) to determine the optimal surrogate marker for assessment of treatment response for each class of therapy. The effectiveness of MR for detection of treatment response in brain tumors will be evaluated in two Specific Aims. MR data from tumors will be compared with efficacy determined using animal survival, changes in tumor volume/growth rates, and histology to determine which specific or combined imaging-observable parameter can be utilized as a surrogate marker for predicting therapeutic outcome. These studies will provide the rationale for pairing a specific imaging surrogate marker with a therapeutic intervention in order to obtain the most effective readout of early treatment response. These rodent imaging studies will serve as the basis for translating and evaluating these approaches in the clinic as proposed in Project #3. Pub. Health: Overall, this research effort will provide the rationale for initiation of clinical trials with combinations of molecularly targeted therapies for the treatment of malignant brain tumors. In addition, imaging biomarkers for early assessment of treatment response will be identified and validated which will lead to individualization of patient treatment.