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Inhibiting Hedgehog signaling pathway may improve pancreatic cancer treatment

LAKE TAHOE, Nev. Combining a new targeted therapy with standard chemotherapy may help defeat pancreatic cancer, according to results presented at the American Association for Cancer Research's Pancreatic Cancer: Progress and Challenges conference, held here June 18-21.

"We believe that GDC-0449 has the potential to change the approach to treating pancreatic cancer," said Edward J. Kim, M.D., Ph.D., a medical oncologist at the University of Michigan Comprehensive Cancer Center in Ann Arbor, Mich.

GDC-0449 targets the Hedgehog signaling pathway. This pathway is normally silent in the adult pancreas but it is switched on in patients with pancreatic cancer and contributes to the desmoplastic stroma that is characteristic of this disease.

"This dense stroma is believed to contribute to resistance to chemotherapy by presenting a physical barrier to chemotherapy delivery," Kim explained.

In addition, Hedgehog levels are increased in pancreatic cancer stem cells. Cancer stem cells are a subset of cancer cells present in a tumor that are believed not only to drive tumor growth by generating bulk tumor cells, but to also be particularly resistant to standard therapies like chemotherapy and radiation.

"Even if a therapy succeeds in obtaining a response, cancer stem cells may persist and contribute to resistance and progression of disease," Kim said. "Having found that pancreatic cancer stem cells have higher Hedgehog levels than bulk cancer cells, we were interested in determining whether targeting the Hedgehog signaling pathway and, therefore, the cancer stem cells might lead to improved outcomes in pancreatic cancer."

GDC-0449 targets the Smoothened (SMO) protein in the Hedgehog signaling pathway. It was approved for use in basal cell carcinoma and is marketed as vismodegib. Kim and his colleagues felt that treating patients with pancreatic cancer first with GDC-0449 and then with the standard chemotherapeutic drug gemcitabine might disrupt the desmoplastic stroma and improve the efficacy of the chemotherapy.

They evaluated this strategy in treatment-naive patients with advanced pancreatic cancer. Patients underwent needle biopsies of the cancer before and after taking GDC-0449 for three weeks to study the effects of GDC-0449 on the Hedgehog pathway signals, tumor stroma and pancreatic cancer stem cells. Gemcitabine was added to GDC-0449 following the second biopsy.

Five patients achieved partial response, and another four patients had stable disease, yielding a 50 percent progression-free survival rate at three months.

"New ways to treat pancreatic cancer are needed to improve response to therapy and ultimately patient outcomes," Kim said, adding that he hopes data from the biopsy specimens will help identify predictive markers to determine who would benefit from this combination treatment.


Contact: Jeremy Moore
American Association for Cancer Research

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