Inhibiting Hedgehog Pathway May Aid in Pancreatic Cancer Treatment

Vismodegib cuts the number of cancer stem cells and improves the effectiveness of chemotherapy.

In a small clinical trial, 5 of 20 patients with advanced pancreatic cancer who received the targeted drug vismodegib (Erivedge; Genentech) with standard chemotherapy experienced a partial response and 5 more achieved stable disease after several treatment cycles—a 50% progression-free survival rate at 3 months. The trial's preliminary findings were reported at the American Association for Cancer Research's Pancreatic Cancer: Progress and Challenges Conference in Lake Tahoe, NV, on June 19.

Vismodegib, approved earlier this year for the treatment of basal cell carcinoma, targets the Smoothened protein in the Hedgehog signaling pathway. Activation of the pathway contributes to the extensive scarring, or desmoplastic stroma, that characterizes pancreatic cancer.

“This dense stroma is believed to contribute to resistance to chemotherapy by presenting a physical barrier to chemotherapy delivery,” explained Edward Kim, MD, PhD, a medical oncologist at the University of Michigan Comprehensive Cancer Center in Ann Arbor, who presented the findings.

In preclinical work, Kim's team showed that Sonic Hedgehog levels are increased in pancreatic cancer stem cells, which are particularly resistant to standard treatments like chemotherapy and radiation. The researchers built on that finding in the current study. They hypothesized that treating patients with daily vismodegib for 4 weeks, followed by ongoing 4-week treatment cycles combining daily vismodegib and 3 infusions of the chemotherapeutic drug gemcitabine, might target the stem cells and disrupt the desmoplastic stroma, thus improving the efficacy of chemotherapy.

As part of the trial, 19 patients had a biopsy before treatment and another after taking vismodegib for 3 weeks. Researchers analyzed the tissue samples to assess the impact on cancer stem cells and found that 11 patients experienced a decrease in these cells. On average, the number of cells decreased by nearly 60%. However, the researchers did not see a clear correlation between changes in the number of cancer stem cells and clinical benefit.

The researchers also teased out predictors of treatment response. “We determined that assessment of pretreatment Sonic Hedgehog levels was the best predictor of treatment response,” said Kim, adding that ongoing studies will identify the patients best suited to benefit from this combination therapy.

“Usually we see about a 5% to 9% chance of having a response to gemcitabine by itself. Here, it was 25%,” said Daniel Von Hoff, MD, a professor of medicine at the University of Arizona College of Medicine and at the Mayo Clinic in Scottsdale, AZ, who has studied Hedgehog inhibitors and commented on the early findings. “I'm very interested to see the final results.”