Targeting Pancreatic Cancer Using Peptide Chemistry: From Bench to Bedside

Pancreatic adenocarcinoma (PCA) remains a fatal disease with extremely poor prognosis, despite advances in the understanding of molecular mechanisms in cancer biology. This may be attributed to the failure in translating the acquired knowledge into viable therapeutics. Towards this end, we have defined a novel regulatory role for the protein GIPC in pancreatic cancer growth and metastasis, and identified it as a plausible target for pancreatic cancer therapy. GIPC binds to various endogenous proteins with its PDZ domain. Our published results suggest that either depletion of GIPC expression, or disruption of PDZ domain- binding between GIPC and endogenous partner proteins (such as IGF-1R or endoglin) via peptide-based inhibitors, elicits a significant inhibitory response in pancreatic cancer growth. We have also shown that pancreatic cancer cells with depleted GIPC expression exhibited an increase in autophagy and exosome biogenesis, and enhanced sensitivity towards the conventional drug gemcitabine. Furthermore, our preliminary data indicate that GIPC binding partners and downstream signaling molecules are differentially regulated in different subgroups of PCA. Taken together, these observations have led us to hypothesize that inactivation of GIPC function, by disrupting the binding of GIPC with subgroup-specific endogenous partner proteins, can be exploited to inhibit signaling pathways important for cancer progression, metastasis and drug resistance in various subgroups of PCA. This would have important clinical implications towards the development of personalized therapy for treating pancreatic cancer. To test our hypothesis, we have proposed two aims. Aim 1 will focus on developing a new generation of highly selective and potent peptide and small molecule inhibitors of GIPC, with the help of NMR spectrometry and X-ray crystallography, the latter which has recently yield the first structure of GIPC bound to one of our inhibitors. Aim 2 will focus on determining how GIPC and its partner proteins differentially regulate various downstream signaling pathways in different subgroups of PCA, and designing new individualized therapy for pancreatic cancer based on the this acquired knowledge. Overall, these studies will help us to develop novel personalized therapeutic strategies for different subgroups of PCA, by combining conventional drugs with newly-developed pathway- specific inhibitors of GIPC, which can be translated to fast track clinical trials in the near future.