Understanding the Cooperation Between LMO1 and MYCN in Neuroblastoma Metastasis Using a Novel Zebrafish Model

Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for ~10% of cancer-related deaths in childhood. About half of all patients, especially those over 18 months of age with amplified copies of the MYCN oncogene, present with evidence of wide hematogeneous metastasis at diagnosis and have a very high risk of treatment failure and death despite greatly intensified chemotherapy. Thus, new efforts to devise safe and effective therapies for this disease are urgently needed and constitute the long-term goal of this proposal. Recently, we developed the first zebrafish model of neuroblastoma metastasis by overexpressing two oncogenes, human MYCN and LMO1. This transgenic model affords unique opportunities to study molecular basis of neuroblastoma metastasis in vivo, and to identify novel genes and pathways that cooperate with MYCN and LMO1 to promote this usually fatal stage of disease development -- the objectives of my research in this application.

As a biomedical researcher, I am particularly motivated by work that has the potential to advance our understanding of cancer toward the development of improved therapeutics. My long-term career goal is to become an independently funded cancer biologist with interests and expertise in tumor metastasis, functional genomics, signal transduction, and translational research. I hope to translate the knowledge gained from my experimental studies into effective therapy for neuroblastoma metastasis. The Career Development Award would provide an ideal funding mechanism for this stage of my career. Importantly, it will facilitate essential advanced training for me to acquire the knowledge base and technical expertise in exploring the mechanisms of neuroblastoma metastasis. The studies described in this proposal represent initial steps toward identifying promising drug candidates by screening for small-molecule compounds that effectively inhibit key genes and pathways involved in neuroblastoma metastasis. Ultimately, I plan to expand the focus of my research program to include genes, pathways, or predictions emerging from my proposed studies in neuroblastoma pathogenesis, as a means to illuminate the mechanisms driving the initial transformation, progression, and metastasis of other types of human cancers.

Current treatments for disseminated neuroblastoma are limited by their toxicity and inability to eradicate distant metastases. Attempts to improve this situation have been impeded by the lack of a detailed understanding of the multistep cellular and molecular pathogenesis of this complex tumor. This proposal combines in vivo functional genomic studies of our novel zebrafish model of neuroblastoma metastasis, together with in vitro biochemical and molecular analyses of human neuroblastoma cell lines, to elucidate how the overexpression of LMO1 collaborates with MYCN to contribute to metastasis in neuroblastoma and to identify key genes or pathways that are pivotal in this process. These comprehensive mechanistic studies will provide critical insights to aid our understanding of neuroblastoma metastasis. We also anticipate that the studies we propose, especially those identifying novel genes and signaling pathways, will uncover molecular targets that can be exploited therapeutically. Indeed, small-molecule inhibitors targeting several candidate LMO1-upregulated genes are now available. Hence, by using the established in vivo zebrafish models of aberrant pathways downstream of LMO1 and MYCN that drive neuroblastoma metastasis, we will have ideal platforms for future screening of small-molecule inhibitors of metastatic neuroblastoma to identify the most effective and least toxic candidates for further development. Together, our studies have the potential to both broaden and deepen our understanding of the synergy between LMO1 and MYCN in neuroblastoma metastasis, which should suggest strategies to inhibit the interaction between these oncogenes and hence their contributions to neuroblastoma metastasis.

Neuroblastoma is the most common cancer in babies younger than 1 year old. Thus, children of military Service members and Veterans are among those at risk of developing disease and would benefit from new targeted therapies and personalized medicine for this devastating disease. The development of neuroblastoma in children of military families carries the added risk of disrupted service time due to the family's involvement in the child's care, especially during emergency episodes.