Box 1. Revisiting the pancreas.

The insights into the nature of these aggressive, poorly differentiated pancreatic tumors suggest a niche for two other classes of cancer treatments-angiogenesis inhibitors and immune checkpoint inhibitors.

Additional data published in the Columbia University Medical Center-Perelman School of Medicine at the University of Pennsylvania study showed that the poorly differentiated tumors in sonic hedgehog homolog (Shh)-deficient or saridegib-treated mice were more vascularized than those from nondeficient mice or vehicle-treated controls.1 In the Shh-/- mice, a VEGF receptor-blocking mAb increased survival compared with IgG control.

Ben Stanger, an assistant professor of medicine at the Perelman School of Medicine, noted that even though antiangiogenic therapies have failed in the overall PDAC patient population, the mouse data in his study suggest that the subset of patients with poorly differentiated tumors could benefit.

"In PDAC, about 10% of the patients have poorly differentiated tumors, and based on what we've seen in our mouse studies, such tumors might also have higher blood vessel density and be more dependent on the vascular network. If this is the case, it might mean that such tumors will be responsive to antiangiogenic therapies," he said.

Meanwhile, The University of Texas MD Anderson Cancer Center researchers showed that depletion of actin α2 smooth aorta muscle (Acta2; a-Sma)-positive myofibroblasts in the mouse PDAC model resulted in a more immunosuppressive tumor microenvironment and increased expression of the immune checkpoint protein Ctla-4 (Cd152) compared with no alteration.2 In the myofibroblast-depleted mice, an anti-CTLA4 mAb decreased PDAC progression and increased survival compared with IgG control.

Raghu Kalluri, chair of the Department of Cancer Biology at MD Anderson, noted that the additional data from his group suggest that stroma depletion could create an immune profile in PDAC tumors that renders them sensitive to inhibitors against CTLA-4 and other immune checkpoint proteins. He said that stratifying patients based on their stroma could help identify those that would benefit most from such therapies.

Data from a Phase II trial published in 2010 showed that monotherapy with the anti-CTLA-4 mAb Yervoy ipilimumab was ineffective in advanced PDAC.7 Bristol-Myers Squibb Co. markets Yervoy to treat unresectable or metastatic melanoma.   -K-JL