Personnel: My interest in medicine and biomedical research has been the driving force in my choice of careers and training programs. Over the past 14 years, my research and training have provided a strong base for this proposed project. Using the zebrafish as a model system, I have studied the regulation of cell movements, cell proliferation, and cell survival during embryonic development; tyrosine phosphatase signaling in neural crest development; and the pathogenic roles of candidate oncogenes in neuroblastoma development. I have also contributed to the elucidation of the mechanism underlying LMO1 upregulation and its predisposing role in neuroblastoma tumorigenesis. Conducting these studies fully prepared me to begin a career as a cell developmental and cancer biologist with a solid background in the use of zebrafish models for in vivo study of cell signaling and neuroblastoma pathogenesis -- one of the Fiscal Year 2016 Peer Reviewed Cancer Research Program Topic Areas. The training opportunity afforded by the Career Development Award will be facilitated under the mentorship of Dr. van Deursen and an advisory committee, including leaders in the field of cancer cell biology (Drs. Van Deursen, Maris and McNiven), cancer metastasis (Dr. McNiven), cancer genomics (Dr. Maris), and pathogenesis and translational investigation of neuroblastoma (Dr. Maris).Career Development: The Career Development Award would provide an ideal funding mechanism for this stage of my career. Importantly, it would facilitate essential advanced training for me to acquire the knowledge base and technical expertise needed to explore the mechanisms of neuroblastoma metastasis, to run a contemporary research laboratory, and to prepare myself to become an independently funded cancer biologist with interests and expertise in tumor metastasis, functional genomics, signal transduction, and translational research.Research: Neuroblastoma is an embryonal tumor that arises in the peripheral sympathetic nervous system (PSNS) 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 neuroblastoma metastatic model by overexpressing human MYCN and LMO1 oncogenes. This transgenic model affords unique opportunities to study the 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.Specific Aim 1: To elucidate mechanisms underlying the in vivo contributions of LMO1 and MYCN overexpression to neuroblastoma metastasis.Specific Aim 2: To identify novel genes and pathways that could act as critical downstream effectors of LMO1 overexpression in cooperation with MYCN to promote neuroblastoma metastasis, using gain- or loss-of-function methods in our transgenic fish model.Study Design: In these two aims, we will use our validated zebrafish model of neuroblastoma metastasis -- combined with state-of-the-art live imaging, tumor cell transplantation, CRISPR-cas9-mediated genome editing, and a novel tissue-specific, conditional doxycycline-regulated system -- to identify key pathways downstream of LMO1 that interact with MYCN in neuroblastoma metastasis. It will also be important to learn whether the novel metastasis-promoting genes identified in this study are continuously required for tumor cell metastasis and survival, thus qualifying them as bona fide “drivers” of neuroblastoma pathogenesis.Impact: Using zebrafish models to understand how the overexpression of LMO1 collaborates with MYCN to contribute to neuroblastoma metastasis, and identifying key genes or pathways involved in this process could advance cancer research in important ways. For example, we expect that dissection of the mechanisms mediating synergistic interactions between LMO1 and MYCN, including key genes and pathways that mediate neuroblastoma metastasis, will reveal a number of molecular targets that could be exploited therapeutically to block the spread of malignant cells. Finally, the information we generated will allow us to establish new reliable in vivo models of aberrant pathways in neuroblastoma, which could then be used to screen for effective small molecule inhibitors of neuroblastoma that have minimal toxicity to normal tissues and thus would have high priority as candidate therapeutic agents.Military Relevance: Neuroblastoma is the most common extracranial solid tumor of childhood, accounting for about 10% of all cancer-related deaths in children. Thus, children of military Service members and Veterans are among those at risk of developing neuroblastoma 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.
|Effective start/end date||8/1/17 → 7/31/20|
- Congressionally Directed Medical Research Programs: $556,500.00