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，我们在提高生存率方面的能力正在达到平台期。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。尽管人们对神经母细胞瘤复发性基因组异常已有30年的了解，但除了神经母细胞瘤癌基因MYCN外，这些异常的基因靶点仍然未知，也没有发现真正的神经母细胞瘤肿瘤抑制基因。一类新的被称为microRNAs （miRNAs）的调节非编码rna的发现，由于其在正常胚胎发育和癌症中的作用，是有吸引力的候选神经母细胞瘤癌基因和肿瘤抑制基因。我们假设致癌和肿瘤抑制microrna （oncomirs）有助于神经母细胞瘤的发生。本提案旨在通过以下方法验证这一点：1)通过综合基因组方法识别神经母细胞瘤肿瘤；2)表征miR-34家族（及其他已确定的肿瘤）在神经母细胞瘤中的抑瘤机制；3)在体内证明miR-34a替代的临床前治疗效果。这项工作的发现将在癌症生物学上有更广泛的应用，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肿瘤中发现。

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.