Neuroblastoma is a devastating childhood cancer. Most children with this disease have features that define their cancer as "high-risk." For these children, treatment includes multiple cycles of chemotherapy, surgery, high-dose chemotherapy with stem cell transplant, radiation therapy, biotherapy, and immunotherapy. Still, survival remains dismal and those cured have substantial long-term toxicities from their treatment. Improvements in survival for this cancer have come slowly, and neuroblastoma is responsible for 1 of every 6 childhood cancer deaths. It is clear that innovative approaches must be discovered.

The last decade of biomedical research has seen an explosion of new genetic information that improves our understanding of cancer behavior. This information is used by researchers worldwide to (1) understand what makes particular cancers behave the way they do, and (2) to exploit this information to improve our treatments. In neuroblastoma we have been working to exploit the observation that most high-risk tumors have "turned on" a critical cell gene called MYC or MYCN. This finding is so integral to high-risk neuroblastoma that treatment groups worldwide search for this gene alteration to assign patients to an appropriately intensive therapy.

How "turning on" an MYC gene in neuroblastoma leads to an aggressive tumor remains unclear. MYC genes themselves control hundreds of other genes that affect cancer cell behavior. Our laboratory has recognized that among these are many genes that control polyamines, a class of molecules essential for cell survival. Polyamines are markedly elevated in cancer tissues (particularly rapidly growing tumors) so we hypothesized they might be important factors in neuroblastoma. We have confirmed that high-risk neuroblastomas alter nearly all of the enzymes that produce polyamines, leading to remarkably elevated cell levels. When we use experimental treatments that interfere with polyamine production (using enzyme inhibitors that may be safely given to children) we cause neuroblastoma cells to die. Remarkably, these same therapeutics can prevent neuroblastoma in a mouse model and substantially improve the effectiveness of standard chemotherapy. Our data clearly support that neuroblastomas are dependent on polyamines and vulnerable to their depletion.

In this grant application we detail plans to optimize this approach and test specific combinations of polyamine inhibitors with currently used chemotherapy drugs. Our results have been very promising and our hope is to develop a regimen most likely to prove successful in clinical studies of children with high-risk neuroblastoma. We work closely with the COG Developmental Therapeutics and the New Approaches to Neuroblastoma Therapy (NANT) groups, so we can rapidly advance these agents into clinical testing. It should also be noted that greater than 50% of cancers are found to have "turned on" MYC genes, so the approach piloted here might prove useful against additional cancer types.