Thursday, June 12, 2014
Box 1. Revisiting 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.
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.
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.
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.
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
compared with no alteration.2 In the myofibroblast-depleted mice, an
anti-CTLA4 mAb decreased PDAC progression and increased survival compared with
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.
a Phase II trial published in 2010 showed that monotherapy with the anti-CTLA-4
was ineffective in advanced PDAC.7
Squibb Co. markets Yervoy to treat unresectable
or metastatic melanoma. -K-JL