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，完成了癌症基因组学的富有成效的博士后指导培训，最近承担了一项独立的翻译任命，临床重点是肉瘤。肉瘤是一种临床和生物学复杂性很高的疾病，在年轻人群中发病率很高，其分子基础知之甚少。申请人使用分析多个公开可用的肉瘤微阵列数据集的先进计算方法生成的初步数据，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检验假设。在具体目标1中，申请人提出在大型肿瘤队列中研究先前发现的分子诊断谱，假设其将比传统组织学分类更好地捕获肉瘤的异质性。此外，他还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途径的激活状态，并打算测试其与治疗结果和反应的相关性。这些途径都是已经在临床试验中的抑制剂的靶向，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3中，申请人将其工作扩展到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中的基因表达、致癌途径和结果的关系，从而以允许出现最佳治疗策略的方式进一步阐明这种疾病的分子背景。将使用先进的计算方法，基于候选人在计算生物学医学应用方面的特殊培训。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，以增加对大型队列的访问，以及更大验证和未来临床应用发现的机会。 该提案和培训将服务于申请人未来的职业目标，成为转化基因组学和系统生物学癌症研究的领导者，临床重点是肉瘤。他将受益于哈佛医学院、贝丝以色列女执事医疗中心和达纳/法伯哈佛癌症中心为他提供的一流癌症研究环境，以及基因组学和肉瘤领域高级顾问的专业知识，以及他将在该奖项的支持下发展的重要合作关系，以及哈佛医学院系统生物学系的教育和科学机会。在不久的将来，该奖项将为他提供关键支持，以建立一个新的疾病重点研究项目，该项目将在未来2-3年内获得独立的NIH级支持。 公共卫生相关性：肉瘤是具有几乎无与伦比的临床、生物学和分子多样性的癌症，不成比例地影响年轻人或儿童。尽管其复杂性，分类和治疗方法，除了罕见的例外，没有先进的近20年。这项拨款提案将利用肿瘤基因组分析的尖端工具来剖析它们的分子复杂性，以便开发新的个性化疗法。

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.