Arginine Depletion with DFMO in High-Risk Neuroblastoma
Despite intensive treatment, about half of all children with high-risk neuroblastoma die of their disease. These aggressive tumors often have a mutated MYCN gene, which drives tumor cell growth by helping them to produce the necessary building blocks for DNA, proteins, and polyamines. Polyamines are essential chemicals created from amino acids like proline and arginine that enable cells to grow and to survive. Tumors with high levels of polyamines behave aggressively and can resist treatment. Arginine is a specific amino acid that plays many other roles in tumor progression, including altering the ability of immune cells to see and kill tumor cells. Many tumors alter their immune environmental surroundings to create a hostile environment that helps them evade the immune system. We study neuroblastoma in genetically modified mice that spontaneously develop high-risk neuroblastomas at places inside the body similar to where they arise in children. These mice have normal immune systems, and their tumors' immune environments are also similar to those in children with neuroblastoma. We have found that inhibiting polyamine production with difluoromethylornithine (DFMO) prolongs mouse survival from neuroblastoma, but all mice eventually die from their tumors. However, when we also remove proline and arginine from their diet when treating with DFMO, we cure more than half of the mice, a finding we have not previously seen. We plan to build upon this previous finding to learn how this treatment cured these mice so we can hopefully apply this knowledge to treating children with neuroblastoma.
Project Goal:
Because of our striking discovery that DFMO and the proline/arginine deficient diet can cure mice with neuroblastoma, this project aims to specifically clarify the role of arginine in blocking neuroblastoma growth. One of our goals is to determine whether a combination of DFMO and a arginine-deficient diet has similar survival results. Our other goal is to characterize the effects of arginine depletion and DFMO upon the immune microenvironment and to determine how it affects the tumor's populations of T cells and NK cells. We will evaluate the effects of this treatment on the immune microenvironment, signaling proteins, and immune cells. If effective, this treatment combination could be translated into a clinical therapeutic regimen to improve the survival of children with high-risk neuroblastoma.
