INTEGRATING OMICS AND QUANTITATIVE IMAGING DATA IN CO-CLINICAL TRIALS TO PREDICT TREATMENT RESPONSE IN TRIPLE NEGATIVE BREAST CANCER

项目摘要 三阴性乳腺癌（TNBC）是一种非常具有挑战性的疾病，因为它在生物学上具有侵袭性， 没有靶向治疗，因此，患者预后不良。虽然免疫疗法是 TNBC在治疗许多癌症方面有希望，但缺乏特定的分子靶点，没有预测性生物标志物， 化疗反应尚未确定，治疗反应很难使用目前的方法进行评估。 生物标志物评估。TNBC的患者来源的异种移植物（PDX）模型提供了令人兴奋的机会， 根据分子特征（例如，基因组拷贝数，整个外显子组序列，和 mRNA表达）以鉴定最佳预测对治疗的最终响应的候选“组学”生物标志物 并且可以提供替代终点以在共同临床试验人体试验中验证新的成像生物标志物。 此外，新兴的定量MRI方法，如动态对比增强磁共振， 磁共振成像（DCE-MRI）和扩散加权MRI（DW-MRI）在图像中包含丰富的生理信号， 预测治疗反应，但整合动物和人类数据以可靠地预测治疗反应是具有挑战性的。 治疗反应。一种“联合临床试验”的模式正在出现，在这种模式中， 动物，结果指导临床试验中的治疗，但缺乏信息学工具和资源 以便能够分析这种动物到人类的工作。我们认为，一个基于信息的方法， 整合分子“组学”和成像数据将推动TNBC的进步， 机器学习模型来预测对治疗的反应。为了开发研究资源， 鼓励就如何优化定量成像方法以提高成像质量达成共识 对于联合临床试验的结果，我们将利用我们正在进行的联合临床试验，以实现以下目标 （1）鉴定预测TNBC患者来源的异种移植物（PDX）中的反应的分子生物标志物; (2)鉴定预测TNBC患者来源的异种移植物中的反应的定量MRI生物标志物;和（3） 在前瞻性联合临床试验中评估我们的信息学工具。我们的研究意义重大， 创新，因为它利用了基础癌症生物学的进步，最先进的成像技术， 信息学方法来开发一种资源，以催化这种重要疾病的发现。我们基于PDX的 该方法将为癌症社区提供合理的，迭代的，结合临床前和临床 方法和支持数据资源，以使治疗逐步更加精细和个性化 TNBC患者的治疗方案。我们的方法和工具也可能推广到其他癌症， 因此，大大有利于所有癌症患者的护理。

Project Summary Triple negative breast cancer (TNBC) is a very challenging disease because it is biologically aggressive, there are no targeted therapies, and, consequently, patients have poor prognosis. Although immunotherapy is promising for treating many cancers, TNBC lacks specific molecular targets, no predictive biomarkers to chemotherapy response have yet been identified, and treatment response is difficult to evaluate using current biomarker assessments. Patient-derived xenograft (PDX) models of TNBC offer the exciting opportunity of evaluating this disease in terms of molecular features (e.g., genomic copy number, whole exome sequence, and mRNA expression) to identify candidate “omic” biomarkers that best predict the ultimate response to treatment and could provide surrogate endpoints to validate novel imaging biomarkers in co-clinical trial human trails. Moreover, emerging quantitative MRI methods, such as dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and diffusion weighted MRI (DW-MRI), contain rich physiological signals in the images for predicting treatment response, but it is challenging to integrate both animal and human data to reliably predict the treatment response. A paradigm of “co-clinical trials” is emerging in which new treatments are evaluated in animals, and the results guide treatments in clinical trials, but there is a paucity of informatics tools and resources to enable analyses in such animal-to-human work. We believe that an informatics-based methodology that integrates molecular `omics' and imaging data will propel advances in TNBC by enabling development of machine learning models to predict the response to therapies. In order to develop research resources that will encourage consensus on how quantitative imaging methods are optimized to improve the quality of imaging results for co-clinical trials, we will leverage an ongoing co-clinical trial we are undertaking to pursue the following specific aims: (1) Identify molecular biomarkers that predict response in TNBC patient-derived xenografts (PDX); (2) Identify quantitative MRI biomarkers that predict response in TNBC patient-derived xenografts; and (3) Evaluate our informatics tools in a prospective co-clinical trial. Our proposed research is significant and innovative because it leverages advances in basic cancer biology, state-of-the-art imaging technologies, and informatics methods to develop a resource to catalyze discovery in this important disease. Our PDX-based approach will provide the cancer community with a rational, iterative, combined pre-clinical and clinical methodology and supporting data resource for making progressively more refined and personalized therapeutic regimens for TNBC patients. Our methods and tools will likely also generalize to other cancers and could, therefore, substantially benefit the care of all cancer patients.