The Role of Mxi1 in the Modulation N-Myc Function in Neuroblastoma

Neuroblastoma is the third most common childhood cancer.  Unfortunately, despite intensive treatment, two-thirds of children with advanced neuroblastoma succumb to their disease.  Current intensive therapies have significant side effects, so new treatment options must be developed to improve outcomes in this devastating disease.  To do so requires a better understanding of how neuroblastoma cells survive in the face of these intensive therapies.  N-Myc is a member of a family of proto-oncogenes (genes capable of leading to cancer development) that are implicated as a cause of several cancers.  It is known that N-Myc plays a central role in the aggressiveness of neuroblastoma tumors.  Children whose neuroblastoma tumors have extra copies of the N-Myc gene (N-Myc amplification) fare worse than children whose tumors have the normal number of N-Myc genes.  However, it is unknown why extra N-Myc leads to poor outcomes.  Mxi1 is a transcription factor related to the Myc family of proteins, however, it counteracts the ability of N-Myc to cause cell growth and proliferation.  In this proposal, we will test the hypothesis that expression of Mxi1 in the cell is important for maintaining control of normal growth, and that N-Myc alters its expression leading to treatment resistance.  Furthermore, we will examine whether Mxi1 can be used to restore sensitivity of neuroblastoma cells to treatment, with the overall goal of finding a mechanism to bypass the effects of N-Myc and improve the outcomes of children with neuroblastoma.