Dissecting sarcoma complexity via innovative microRNA and informatics approaches

描述（由申请人提供）：本申请为Dimitrios Spentzos博士提供过渡性支持，他是一名初级研究员，在癌症基因组学方面完成了富有成效的指导博士后培训，最近接受了一项独立的肉瘤临床转译任命。肉瘤是一种具有大量临床和生物学复杂性的疾病，在年轻人群中发病率高，其分子基础知之甚少。申请人使用先进的计算方法分析多个公开可用的肉瘤微阵列数据集生成的初步数据，生成了与结果和靶向治疗相关的改进的肉瘤分子分类的可测试假设。在具体目标1中，申请人建议研究先前在大型肿瘤队列中发现的分子诊断谱，假设它将比传统的组织学分类更好地捕捉肉瘤的异质性。此外，他提出了一种新的分类方案，该方案基于使用表达谱同时评估几种通路的激活状态，并打算测试其与结果和治疗反应的关联。这些途径都是已经在临床试验中的抑制剂靶向的，尽管没有办法优先考虑合适的患者进行研究，因此这项工作为未来的个性化治疗和合理的靶向药物开发提供了基础。在目标2和目标3中，申请人将把他的工作扩展到microRNA水平，并将测试microRNA激活或表达水平与人类软组织肉瘤和骨肉瘤的基因表达、致癌途径和结果的关系，从而进一步阐明这种疾病的分子背景，从而使最佳治疗策略得以出现。根据候选人在计算生物学的医学应用方面的特殊培训，将使用先进的计算方法。此外，基于可靠的初步可行性数据，石蜡肉瘤组织将用于本研究，以增加对大量未选择队列的访问，以及更大规模验证和未来临床应用发现的机会。

DESCRIPTION (provided by applicant): This application proposes transitional support for Dr Dimitrios Spentzos, a junior investigator who completed a productive mentored post doctoral training in cancer genomics, and recently assumed an independent translational appointment with a clinical focus in sarcoma. Sarcoma is a disease with a substantial clinical and biologic complexity and high incidence in younger populations, the molecular underpinnings of which are poorly understood. Preliminary data generated by the applicant using advanced computational methods of analyzing multiple publicly available sarcoma microarray datasets, generated testable hypotheses on improved molecular classification of sarcoma with relevance to outcome and targeted therapeutics. In Specific aim 1, the applicant proposes study a previously discovered molecular diagnostic profile in a large tumor cohort, hypothesizing that it will capture the heterogeneity of sarcomas better than traditional histologic classification. In addition, he proposes a novel classification scheme based on simultaneous assessment of activation status of several pathways using expression profiling, and intends to test its association with outcome and response to therapy. These pathways are all targeted by inhibitors that are already in clinical trials albeit without the means to prioritize appropriate patients for their study, thus this work provides the basis for future personalized therapy and rational targeted drug development. In Aims 2 and 3 the applicant will extend his work to the microRNA level and will test the relationship of microRNA activation or expression levels, with gene expression, oncogenic pathways, and outcome in human soft tissue sarcoma and osteosarcoma, thus further elucidating the molecular context of this disease in a manner that allows optimal therapeutic strategies to emerge. Advanced computational methods will be used, based on the candidate's exceptional training on medical applications of computational biology. Also, based on solid preliminary feasibility data, paraffin sarcoma tissue will be used for this study in order to increase access to large unselected cohorts, and the chance of larger validation and future clinical application of discoveries. This proposal and the training will serve the future career goals of the applicant, to become a leader in translational genomics and Systems Biology cancer investigation, with a clinical focus in sarcoma. He will benefit from the superb cancer research environment available to him at Harvard Medical School, Beth Israel Deaconess Medical Center and Dana/Farber Harvard Cancer Center, and from the expertise of senior advisors in both the genomics and sarcoma fields, aw well as the critical collaborative relationships that he will develop with the support of this Award, and the educational and scientific opportunities within the Systems Biology Department at Harvard Medical School. In the immediate future, this Award will provide critical support for him to establish a research program in a new disease focus that will be competitive for independent NIH-level support in the next 2-3 years. PUBLIC HEALTH RELEVANCE: Sarcomas are cancers with almost unparalleled clinical, biologic and molecular diversity that disproportionately affect young adults or children. Despite their complexity, classification and therapeutic approaches, with rare exceptions, have not advanced in almost 20 years. This grant proposal will utilize cutting-edge tools of tumor genomic analysis to dissect their molecular complexity so that novel personalized therapies can be developed.