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，因为它具有生物学侵袭性。 没有针对性的治疗，因此，患者的预后很差。虽然免疫疗法是 TNBC有望治疗多种癌症，但缺乏特定的分子靶点，也没有可预测的生物标志物 化疗反应尚未确定，治疗反应很难用目前的方法进行评估。 生物标记物评估。患者来源的异种移植(PDX)模型为TNBC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 M RNA表达)来确定最能预测最终治疗反应的候选“基因组”生物标记物 并可以提供替代终点，以在共同临床试验的人体试验中验证新的成像生物标记物。 此外，新兴的定量磁共振方法，如动态对比增强磁共振 成像(DCE-MRI)和弥散加权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。一种“联合临床试验”的范例正在出现，在这种范例中，新的治疗方法被评估 动物，结果指导临床试验的治疗，但缺乏信息学工具和资源 以便在这种从动物到人类的工作中进行分析。我们认为，一种基于信息学的方法 整合分子组学和成像数据将推动TNBC的进展，使其能够 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 结果对于联合临床试验，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 具体目标：(1)识别预测TNBC患者来源的异种移植物(PDX)反应的分子生物标志物； (2)确定可预测TNBC患者来源的异种移植物反应的定量MRI生物标志物；以及(3) 在一项预期的联合临床试验中评估我们的信息学工具。我们提出的研究是有意义的 创新是因为它利用了基础癌症生物学的进步，最先进的成像技术，以及 信息学方法开发一种资源来催化对这种重要疾病的发现。我们基于PDX的 方法将为癌症社区提供合理的、迭代的、临床前和临床相结合的 使治疗逐步精细化和个性化的方法和支持数据资源 针对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，并可能， 因此，大大有益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.