Mechanisms of Gastrin-Releasing Peptide-Mediated Neuroblastoma Growth

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DESCRIPTION (provided by applicant): My research interests center on the study of the G-protein coupled receptor (GPCR) signaling mechanisms involved in the pathogenesis of pediatric extracranial solid tumor cell proliferation. Neuroblastoma is the most common pediatric extracranial solid tumor in infants and children. Despite current advances in therapy, the overall mortality for all stages of the tumor remains at 50%. As a neuroendocrine tumor, neuroblastoma secretes and responds to various gastrointestinal peptides. We and others have previously shown that gastrin-releasing peptide (GRP), by binding to a GPCR, acts as an autocrine/paracrine growth factor for neuroblastoma cells. We also identified that more aggressive, undifferentiated neuroblastomas express increased GRP receptor (GRPR) protein. The phosphatidylinositol 3-kinase (PI3K) is a key cell survival pathway that has recently been demonstrated to be an important signaling mechanism in various cancers. We have reported decreased expression of PTEN, the negative regulator of PI3K, in undifferentiated neuroblastomas. Our studies have also revealed that GRP activates this pathway. Based on our preliminary findings, the central hypothesis of this proposal is that GRP can regulate the growth of neuroblastoma through PI3K pathway activation. To investigate our hypothesis, we have planned the following Specific Aims: 1) to further determine the downstream phenotypic effects of the GRP/GRPR signaling pathway on neuroblastoma cell growth, and 2) to identify the molecular mechanisms regulating GRP-induced PI3K activation. A better understanding of the cellular mechanisms and signaling pathways involved in GRP-induced neuroblastoma cell proliferation could result in the development of novel agents to enhance treatment of this near-fatal disease. Relevance Neuroblastoma is a common childhood cancer derived from cells of neural crest origin; it usually occurs in the adrenal gland in children under three years old. In spite of the advances in treatment options, patients with neuroblastoma still have a staggering mortality rate of 50%. This research is clinically significant because it will enhance our knowledge on this childhood cancer and could provide a breakthrough in the treatment of this devastating tumor.