Grants - V Scholar Grants - Minnesota - 2015

Shizhen (Jane) Zhu, M.D., Ph.D.

Funded by 2015 Dick Vitale Gala

in honor of Leah Still

Neuroblastoma, an embryonal tumor that arises in the peripheral sympathetic nervous system (PSNS), 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 widespread metastasis at diagnosis and have a very high risk of treatment failure and death despite receiving greatly intensified chemotherapy. Attempts to improve the treatment of metastatic neuroblastoma have been slowed by the lack of a full understanding of the multistep cellular and molecular pathogenesis of this complex tumor. Recently, I developed the first zebrafish model of neuroblastoma metastasis by overexpressing two oncogenes, human MYCN, which is amplified in 20% of neuroblastoma cases, and mutationally activated SHP2, which is the second most frequently mutated gene in high-risk neuroblastoma. 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 activated SHP2 to promote this usually fatal stage of disease development. This research approach is expected to reveal novel molecular targets that can be exploited therapeutically. To achieve this goal, I propose to establish reliable in vivo zebrafish models of the aberrant genes and pathways that contribute to neuroblastoma metastasis. In the near future, these models will be used to screen for effective small molecule inhibitors that block specific steps in metastasis with only minimal toxicity to normal tissues, and thus would be assigned high priority as candidate therapeutic agents.