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， 以提高生存率。因此，未来的治疗策略必须合理 利用已知的肿瘤特异性改变。尽管有三十年的知识， 神经母细胞瘤中的异常，除了神经母细胞瘤癌基因MYCN，这些基因的靶点 畸变仍然是未知的，没有真正的神经母细胞瘤肿瘤抑制基因已经被发现。 鉴定发现一类新的调节性非编码RNA，称为microRNA（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。我们假设致癌和抑癌microRNAs （oncomir）有助于神经母细胞瘤肿瘤发生。本提案旨在通过以下方式对此进行测试：1）识别 神经母细胞瘤癌通过整合基因组方法，2）表征肿瘤抑制因子 miR-34家族（和其他鉴定的癌基因）在神经母细胞瘤中的作用机制; 体内miR-34 a替代的临床前治疗功效。这项工作的发现将 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改变是 也见于其他儿童和成人实体瘤。 该提案提出了一项为期5年的研究和培训计划，其最终目标是将校长 一个独立的R 01资助的医生-科学家。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。她会充分利用 她的环境资源，无论是在费城儿童医院和在大学 宾夕法尼亚 相关性（参见说明）： 大多数儿童神经母细胞瘤有高风险的疾病和生存率为这些患者的仍然较少 超过40%，尽管加强了细胞毒性治疗。治愈率的进步将来自于全新的 基于恶性成神经细胞中存在的基本改变的治疗策略。我们提出 通过整合基因组学方法鉴定致癌和抑癌miRNA， 进一步表征它们以转化为用于患有高风险神经母细胞瘤的儿童的新疗法。

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.