200 Hawkins Drive
Iowa City, Iowa 52242
06/28/2011

Aim 1: Perform comparative oncogenomic anaiyses across the human-mouse species barrier of childhood B-lineage tumors, on the one hand, and tumor cell lines and primary tumor samples from double-transgenic LMP1/MYC mice, on the other. Methods involve global gene expression profiling on Affymetrix microarrays, survey of copy number changes across the human and mouse oncogenomes, and bioinformatics approaches including GeneGo analyses.

Literature suggests that cranial radiation portends an increased risk for early development of cardiovascular risk factors, insulin resistance, and the metabolic syndrome. In adults, metabolic syndrome is known to be associated with premature heart disease, type 2 diabetes mellitus, and cardiovascular mortality. The core features of metabolic syndrome include lipid disorder, elevated blood pressure, central obesity, and insulin resistance. These late effects can have dramatic effect on quality of life and life expectancy. Cardiovascular disease can be the result of direct cardiovascular damage caused by cancer treatment or of accelerated atherosclerosis related to cancer treatment. Metabolic syndrome may represent the connection between childhood cancer survivorship and increased long-term risk of cardiovascular disease, particularly in brain tumor survivors.

Aim 2: Study drug responses in LMP1/MYC-induced tumor cell lines and primary and transplanted B-cell lymphomas in LMP1/MYC-transgenic C57BL/6 mice. Methods include 1sF-fluorodeoxyglucose positron emission tomography (FOGPET; indicator of enhanced metabolism of tumor cells) and 1sFfluorodeoxythymicline PET (FLT-PET; indicator of cellular proliferation) to monitor treatment responses in mice objectively and reproducibly.

Expected outcomes and deliverables:

Although standard chemotherapy regimens for Burkitt’s lymphomas can induce remissions in 80% of patients, the therapy is toxic. Both chemotherapy and the biology of the lymphoma or leukemia (high cell turnover) put patients at high risk for tumor lysis syndrome, which may lead to renal failure among other complications. Pediatric patients usually need much higher chemotherapy doses and dose escalations than adult patients, putting the former at a higher risk of toxicity. Therefore, there is a clear need to deveiop less toxic and more targeted therapies for children with B-lineage cancers. Our first aim supplements studies on the LMP1/MYC mouse model of human Burkitt's lymphoma going on in the Bishop laboratory. It is anticipated to determine genomic parameters important for preclinical testing of new childhood cancer therapies in mice. Our second aim will begin with pre~clinical drug testing, using an experimental proteasome inhibitor and FDG-PET as principal experimental methods.