CXCR2 and RET Single Nucleotide Polymorphisms in Pancreatic Cancer

Enhanced angiogenesis and perineural invasion are markers of poor prognosis in patients with pancreatic cancer. Systemic therapies for pancreatic cancer have been largely ineffective, and thus improved, targeted therapies are needed. Single nucleotide polymorphisms (SNP) are DNA sequence variations that result in vast diversity of disease susceptibility and response to disease. CXCR2 is an important mediator of CXC chemokine-induced angiogenesis and is upregulated in pancreatic cancer. In a preclinical corneal micropocket assay, treatment of pancreatic cancer cell lines that express CXCR2 with anti-CXCR2 antibody inhibited angiogenesis. To date, there have not been any CXCR2 SNP associated with pancreatic cancer, but CXCR2 SNP has been postulated to be associated with angiogenesis in systemic sclerosis. The receptor tyrosine kinase encoded by the RET gene and its ligand glial derived neurotrophic factor (GDNF) are upregulated in pancreatic cancer. In vitro treatment of pancreatic cancer cell lines that express RET with anti-RET antibody or RET siRNA-inhibited GDNF-induced invasiveness. G691S RET SNP has been previously shown to be associated with enhanced pancreatic cancer invasiveness. We suggest that molecular profiling of each patient’s tumor for G691S RET SNP, potentially CXCR2 SNP, and also other yet-to-be identified SNP associated with pancreatic cancer will allow for both improved understanding of individual prognosis and allow for utilization of more personalized, targeted adjuvant therapies. This work was presented at the Molecular Surgeon Symposium on Personalized Genomic Medicine and Surgery at the Baylor College of Medicine, Houston, TX, USA, April 12, 2008. The symposium was supported by a grant from the National Institutes of Health (R13 CA132572 to Changyi Chen).