Neuroblastoma is a common and frequently lethal tumor of childhood. Amplification and over-expression of MYCN correlates with aggressive high-risk disease. We generated a model for high-risk neuroblastoma by directing expression of a MYCN transgene to the peripheral neural crest of transgenic mice, under control of the Tyrosine Hydroxylase (TH) promoter. We hypothesize that Mycn plays a central role in tumor maintenance, and that therapies targeting Mycn in-vivo will be effective MYCN-amplified neuroblastoma. Newly diagnosed neuroblastoma typically responds to conventional chemotherapy. In high-risk patients, tumor relapse is inevitable, and is associated with resistance to therapy. Mutation in p53 is uncommon in tumors at diagnosis, but is observed at relapse, and may underlie drug resistance. We secondarily hypothesize that GEM mice transgenic for TH-MYCN and deleted forp53 model high-risk, therapy-resistant neuroblastoma in relapsed patients, and that these tumors will respond to small molecule inhibitors targeting Mycn. In this competing renewal, we will first evaluate mice transgenic for MYCN and mutant for p53 as a model for relapsed, drug-resistant human neuroblastoma. Second, we will test the mice transgenic for MYCN and wt vs mutant at p53. We hypothesize that these compounds will be effective and safe in patients with MYCN-amplified neuroblastoma. Third, we will utilize these P13-kinase inhibitors to block Mycn in-vivo, to address Mycn's role in maintaining angiogenesis in-vivo. Mycn has an established role in angiogenesis. We therefore hypothesize that the efficacy of Mycn blockade in neuroblastoma stems in part from disruption of angiogenesis.
Aim 1 evaluates mice transgenic for TH-MYCN and mutant for p53 as a platform for preclinical developmental therapeutics in relapsed, drug-resistant neuroblastoma.
Aim 2 tests whether a class of drugs that target Mycn should be developed for clinical use in children with neuroblastoma.
Aim 3 evaluates a role for MYCN in maintaining angiogenesis in murine neuroblastoma, determines how therapies that disrupt Mycn impact this process, and evaluates the importance of p53 in effectiveness of anti-angiogenic therapies. ? ? ?
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