Abstract 2883: Genetic reduction of circulating IGF-1 inhibits growth of COX-2- and Kras-induced pancreatic tumors in orthotopic transplant models

Chronic pancreatitis dramatically increases the risk of pancreatic cancer, the 4th deadliest malignancy in the US. KRAS mutations, the predominant genetic lesion found in pancreatic cancer, are detectable in 30% of patients with chronic pancreatitis. We previously found that calorie restriction (CR) protected against the tumorigenic effects of chronic pancreatitis in the cyclooxygenase (COX)-2-driven (BK5.COX-2) transgenic mouse model of pancreatic cancer. The protection conferred by CR was associated with dramatically reduced circulating levels of insulin-like growth factor (IGF)-1, an established mitogen in a variety of cancer cell lines. We hypothesized that circulating IGF-1 levels have a crucial role in tumor progression in both pancreatitis- and KRAS-induced pancreatic cancer. To test this, mouse pancreatic cancer cells derived from either a BK5.COX-2 transgenic mouse (JC101) or a KrasG12D/INK4a+/− mouse (NB508) were orthotopically transplanted in liver-specific IGF-1-deficient (LID, n=16 per cell line) and wild-type (WT, n=11 per cell line) mice. LID mice were randomized to receive Alzet miniature osmotic pumps (implanted subcutaneously) continuously infusing either vehicle (n=8) or 1 µg/hr of recombinant human IGF-1 (rhIGF-1, Increlex®, Tercica, Inc., Brisbane, CA; n=8). WT mice were infused with vehicle. Mice were euthanized 28 days after tumor and pump implantation, and blood was collected and tumors were weighed and fixed in 10% normal buffered formalin. Immunohistochemical staining for Ki-67 was performed on paraffin-embedded tumors to assess proliferation. In LID mice serum IGF-1 levels were reduced approximately 70% relative to WT (p