Abstract PR2: Therapeutic intervention targeting a Hedgehog-dependent barrier to drug delivery in pancreatic cancer

Ductal pancreatic tumors are unusually resistant to chemotherapy, exhibiting primary resistance to each of the numerous regimens tested to date. These tumors are also unusually desmoplastic and harbor a sparse and inefficient vasculature. The resulting lack of perfusion appears to play a role in the inefficient delivery of numerous chemotherapeutic agents to the parenchyma of pancreatic tumors. Recent evidence has implicated the sonic hedgehog pathway in promoting desmoplasia through a paracrine signaling mechanism active in pancreatic tumors of both humans and the Kras/p53/PdxCre (KPC) mouse model. We sought to evaluate the dependence of stromal desmoplasia on Hedgehog (Hh) pathway signaling and, by extension, assess the effects of Hh pathway inhibition on drug delivery and chemoresistance. Using IPI-926, a semisynthetic inhibitor of the Smoothened protein, we found that stromal contribution was markedly diminished within 10 days of inhibition of the Hh pathway. Paradoxically, the depletion of stromal cells was coincident with an increase in microvessel density, despite previous data indicating a pro-angiogenic role for the Hh pathway. These non-cell autonomous changes resulted in an increase in the delivery of small molecules to KPC pancreatic tumors and an increase in apoptosis when administered in combination with gemcitabine. Ultimately, mice treated with both IPI-926 and gemcitabine had a significant extension of survival and a decrease in the incidence of liver metastases. We conclude that the Hh pathway plays an important role in the maintenance of pancreatic tumor stroma and that this contributes to the primary chemoresistance of pancreatic tumors. These data also support the clinical evaluation of agents that target the stroma in pancreatic cancer. Citation Information: Clin Cancer Res 2010;16(14 Suppl):PR2.