Translational Genomics of MicroRNAs in Neuroblastoma

神经母细胞瘤仍然是儿童中最致命的癌症之一，我们的能力正在达到一个平台期 随着治疗强度的增加而提高存活率。因此，未来的治疗策略必须理性 利用已知的肿瘤特异性改变。尽管轮回基因组知识已有30年的历史 神经母细胞瘤中的异常，除神经母细胞瘤癌基因MYCN外，这些基因的靶点 异常仍不清楚，也没有真正的神经母细胞瘤肿瘤抑制基因。 已确认身份。发现了一类新的调节性非编码RNA，称为microRNAs(MiRNAs) 有吸引力的候选神经母细胞瘤癌基因和肿瘤抑制基因，因为它们在正常 胚胎发育和癌症。我们假设致癌和肿瘤抑制基因microRNAs (Oncomars)促进神经母细胞瘤的发生。这项提议试图通过1)确定 神经母细胞瘤通过整合基因组的方法发生，2)肿瘤抑制因子的特征 神经母细胞瘤中miR-34家族(和其他已识别的肿瘤)的机制和3)演示 MiR-34a体内置换的临床前疗效。从这项工作中取得的发现将 在癌症生物学中有更广泛的应用，因为在神经母细胞瘤中发现的许多基因组变化 在其他儿童和成人实体瘤中也有发现。 这项建议列出了一个为期5年的研究和培训计划，最终目标是将校长 一位由R01资助的独立内科医生兼科学家的研究员。她的导师和顾问都是 神经母细胞瘤、翻译基因组学和基因治疗领域。她会利用这个充裕的 她在费城儿童医院和费城大学的环境资源 宾夕法尼亚州。 相关性(请参阅说明)： 大多数患有神经母细胞瘤的儿童疾病风险很高，这些患者的存活率仍然较低 超过40%，尽管加强了细胞毒治疗。治愈率的进步将来自于全新的 基于恶性神经母细胞存在的基本改变的治疗策略。我们建议 通过综合基因组学方法鉴定致癌基因和肿瘤抑制基因miRNAs，并 进一步描述它们的特征，以便转化为治疗高危神经母细胞瘤儿童的新疗法。

Neuroblastoma remains one of the deadliest cancers in children and we are reaching a plateau in our ability to improve survival with increasing intensity of therapy. Thus, future treatment strategies must rationally exploit known tumor specific alterations. Despite thirty years of knowledge of recurrent genomic abnormalities in neuroblastoma, other than the neuroblastoma oncogene MYCN, the gene targets of these aberrations has remained unknown, and no bona-fide neuroblastoma tumor suppressor genes have been identified. The discovery of a new class of regulatory non coding RNAs called microRNAs (miRNAs) are attractive candidate neuroblastoma oncogenes and tumor suppressor genes because of their role in normal embryonic development and in cancer. We hypothesize that oncogenic and tumor suppressor microRNAs (oncomirs) contribute to neuroblastoma tumorigenesis. This proposal seeks to test this by 1) Identifying neuroblastoma oncomirs through an integrative genomic approach, 2) Characterizing the tumor suppressor mechanism of the miR-34 family (and other identified oncomirs) in neuroblastoma and 3) Demonstrating preclinical therapeutic efficacy of miR-34a replacement in vivo. The discoveries made from this work will have broader application to cancer biology as many of the genomic alterations found in neuroblastoma are also found in other pediatric and adult solid tumors. This proposal lays out a 5-year research and training program with the ultimate goal to transition the principal investigator to an independent R01-funded physician-scientist. Her mentors and advisors are leaders in the field of neuroblastoma, translational genomics and gene therapy. She will take advantage of the ample resources of her environment, both at the Children's Hospital of Philadelphia and at the University of Pennsylvania. RELEVANCE (See instructions): Most children with neuroblastoma have high risk disease and survival rates for these patients' remains less than 40%, despite intensification of cytotoxic therapy. Advances in cure rates will result from radically new treatment strategies based on the fundamental alterations present in the malignant neuroblast. We propose to identify oncogenic and tumor suppressor miRNAs through an integrative genomics approach and to further characterize them for translation into novel therapies for children with high risk neuroblastoma.