Stromal uncertainties in pancreatic cancer
Despite the clear rationale for using hedgehog inhibitors in pancreatic cancer-they deplete the stroma to improve chemotherapy delivery-clinical results have been disappointing. New data suggest that the large amounts of stroma surrounding some pancreatic cancers might actually have protective properties.1,2
The findings could explain the negative clinical data for some hedgehog inhibitors in pancreatic cancer, but it remains to be seen whether the cautionary tale applies to other classes of stroma-depleting therapies. In addition, the data provide a rationale to retry two other classes of cancer drugs in pancreatic cancer-angiogenesis inhibitors and immune checkpoint inhibitors (see Box 1, "Revisiting the pancreas").
Pancreatic ductal adenocarcinomas (PDACs) account for the majority of pancreatic cancers. PDACs usually have poor perfusion and vascularization and often are surrounded by abundant stroma, which is thought to supply factors that support tumor growth and hinder drug delivery.3
In 2009, an international team led by researchers at Cancer Research UK published preclinical data in Science suggesting that hedgehog pathway inhibitors could deplete the tumor stroma. The group showed that the small molecule smoothened (SMO) inhibitor saridegib (IPI-926) from Infinity Pharmaceuticals Inc. enhanced delivery of the chemotherapeutic gemcitabine and improved survival in mouse models of PDAC.4
SMO is a key mediator of hedgehog pathway signaling.
The following year, Infinity began a Phase I/IIb trial of saridegib plus