Study shows how to defeat chemotherapy barrier in pancreatic cancer

Scientists at Fred Hutchinson Cancer Research Center and the Translational Genomics Research Institute (TGen) have discovered a literal 'break through' in pancreatic cancer.

A unique biological barrier that pancreatic cancer tumors build around themselves have made them especially resistant to chemotherapy treatments, according to the Hutchinson Center/TGen study published today in the highly-regarded journal Cancer Cell.

Pre-clinical experiments show that a combination of drugs could break down the barrier surrounding these tumors, allowing chemotherapy drugs to freely spread and permeate throughout the cancerous tissue, according to the study.

"Discovering how to break through this barrier is a significant finding that could eventually enable therapeutic compounds to be much more effective in combating this deadly cancer and helping patients," said Dr. Daniel Von Hoff, M.D., TGen's Physician-In-Chief and one of the authors of the study, as well as one of the world's leading authorities on pancreatic cancer.

"The barrier surrounding pancreatic ductal adenocarcinoma has prevented therapeutics from reaching and effectively acting on this cancer," said Dr. Von Hoff, who also is head of TGen's Clinical Translational Research Division.

This research is now being tested for the first time in patients in the U.S. and Europe, including those at Seattle Cancer Care Alliance, the Hutchinson Center's patient treatment arm. These tests have the potential to significantly increase the length of survival in patients with pancreatic cancer, which is notoriously fast-spreading and among the most lethal of all cancers, the study says.

Dr. Sunil Hingorani, M.D., Ph.D., the study's senior author and an associate member of the Hutchinson Center's Clinical Research and Public Health Sciences divisions, developed the study's laboratory model. By combining gemcitabine - the current standard chemotherapy used to treat patients' pancreatic ductal adenocarcinomas - with an enzyme called PEGPH20, scientists showed that the tumor barrier could be broken down and the drug could more easily reach the cancerous tissue.

"This represents the largest survival increase we've seen in any of the studies done in a preclinical model, and it rivals the very best results reported in humans," Dr. Hingorani said. "Being able to deliver the drugs effectively into the tumor resulted in improved survival as well as the realization that pancreas cancer may be more sensitive to conventional chemotherapy than we previously thought."

Unlike most solid tumors, pancreas tumors use a two-pronged defense to keep small molecules, such as those contained in chemotherapy, from entering: a vastly reduced blood supply and the creation of a strong fibro-inflammatory response. The latter includes the production of fibroblasts, immune cells and endothelial cells that become embedded within a dense and complex extracellular matrix throughout the tumor. One major component of this matrix is a substance called hyaluronan, or hyaluronic acid (HA). HA is a glycosaminoglycan, a complex sugar that occurs naturally in the body and is secreted at extremely high levels by pancreatic cancer cells.

Dr. Hingorani, Dr. Von Hoff and their colleagues discovered that the fibro-inflammatory response creates unusually high interstitial fluid pressures that collapse the tumor's blood vessels. This in turn prevents chemotherapy agents from entering the tumors. The researchers found that HA is the main biological cause of the elevated pressures that leads to blood vessel collapse.

Administering the enzyme/gemcitabine combination degrades HA in the tumor barrier and results in rapid reduction of the interstitial fluid pressure. This in turn opens the blood vessels and permits high concentrations of chemotherapy to reach the tumor.