Translational Genomics of MicroRNAs in Neuroblastoma

描述（由申请人提供）： 神经母细胞瘤仍然是儿童中最致命的癌症之一，随着治疗强度的增加，我们提高生存率的能力正在达到一个平台。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。尽管对神经母细胞瘤中复发性基因组异常的了解已有三十年，但除了神经母细胞瘤癌基因MYCN之外，这些异常的基因靶点仍然未知，并且没有真正的神经母细胞瘤肿瘤抑制基因被鉴定。一类新的称为microRNA（miRNAs）的调节性非编码RNA的发现是有吸引力的候选成神经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中的作用。我们假设致癌和抑癌microRNA（oncomirs）有助于神经母细胞瘤的肿瘤发生。该提案试图通过以下方式来测试这一点：1）通过整合基因组方法鉴定神经母细胞瘤体; 2）表征神经母细胞瘤中miR-34家族（和其他鉴定的瘤体）的肿瘤抑制机制;和3）证明miR-34 a替代在体内的临床前治疗功效。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也在其他儿科和成人实体瘤中发现。 该提案提出了一项为期5年的研究和培训计划，最终目标是将主要研究者转变为独立的R 01资助的医生科学家。她的导师和顾问是神经母细胞瘤，翻译基因组学和基因治疗领域的领导者。她将充分利用她的环境，无论是在费城儿童医院和宾夕法尼亚大学的丰富资源。 相关性：大多数患有神经母细胞瘤的儿童具有高风险疾病，尽管加强了细胞毒性治疗，这些患者的存活率仍然低于40%。治愈率的进步将来自于基于恶性成神经细胞中存在的根本改变的全新治疗策略。我们建议通过整合基因组学方法鉴定致癌和抑癌miRNAs，并进一步表征它们，以将其转化为高危神经母细胞瘤儿童的新疗法。

DESCRIPTION (provided by applicant): 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: 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.