Study reported in Science in mice suggests combination with hedgehog signaling therapies may be more effective.

Naturally poor vasculature in pancreatic tumors may prevent chemotherapy drugs such as gemcitabine from reaching the tumor and be at least partly responsible for the cancer’s resistance to treatment, claims an international team of researchers led by scientists at Cancer Research UK’s Cambridge Research Institute.

The scientists’ studies with a new, genetically modified mouse model of pancreatic cancer also suggest that antiangiogenic drugs like VEGF inhibitors are often less effective in pancreatic cancer than other tumor types because pancreatic tumors don’t need such a good blood supply to survive.

Subsequent research by the team found that combining gemcitabine with a different type of drug such as Infinity Pharmaceuticals’s hedgehog signaling pathway inhibitor candidate, IPI-926, may represent a more effective treatment against pancreatic cancer. Currently in a Phase I trial in patients with advanced and/or metastatic solid tumors, IPI-926 is a second-generation, semisynthetic cyclopamine deriviative.

The findings were published on May 21 in Science in a paper called “Inhibition of Hedghog Signaling Enhances Delivery of Chemnotherapy in a Mouse Model of Pancreatic Cancer.”

The researchers found that the mice were largely resistant to gemcitabine therapy, because their tumors had poor networks of blood vessels. They subsequently found that human pancreatic cancer samples also had a deficient blood supply, similar to that of the gemcitabine-resistant mouse model. In contrast, transplantation mouse models traditionally used in the development of cancer chemotherapies were sensitive to gemcitabine.

When the mice were treated with a combination of gemcitabine and IPI-926, there was an increase in cell death and a reduction in the animals’ pancreatic tumor size. The scientists claim these data may reopen the door to new treatments which have to date proved disappointing in human trials due to poor drug delivery.

The Cancer Research UK team, funded by the Lustgarten Foundation and the NIH, worked with groups at the U.K.’s Addenbrooke’s Hospital, the Johns Hopkins Hospital, the University of Dresden, the University of Texas MD Anderson Cancer Centre, University of Pittsburgh, and the Fred Hutchison Cancer Research Center.

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