Monday, May 21, 2012

Blasting Pancreas Cancer Treatment Barriers



Pancreas cancer tumors spread quickly and are notoriously resistant to treatment, making them among the deadliest of malignancies. Their resistance to chemotherapy stems in part from a unique biological barrier the tumor builds around itself. Now scientists at Fred Hutchinson Cancer Research Center have found a way to break through that defense, and their research represents a potential breakthrough in the treatment of pancreas cancer.

In a paper published March 2012 in Cancer Cell, senior author Sunil Hingorani, M.D., Ph.D., an associate member of the Hutchinson Center's Clinical Research and Public Health Sciences divisions, and colleagues describe the biological mechanisms of how the tumor barrier is formed and detail a newly discovered way to break it down. Their research significantly increased the length of survival in a genetically engineered mouse model of the disease. Early clinical trials in humans are under way at a few sites in the U.S. and Europe, including Seattle Cancer Care Alliance, the Hutchinson Center's patient treatment arm.

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Using a mouse model developed by Hingorani, the scientists combined gemcitabine, the current standard chemotherapy used to treat pancreatic ductal adenocarcinomas (PDA), with an enzyme called PEGPH20. When they infused the combination into specially engineered mice whose pancreas tumors mimic those of human pancreas cancer, the combination broke down the matrix barrier within the tumors and allowed the chemotherapy to permeate freely and spread throughout the cancerous tissue. The result was a 70 percent increase in survival time of the mice after the start of treatment, from 55 to 92 days.

"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," Hingorani said.

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 fibroinflammatory 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 pancreas cancer cells.

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Hingorani and colleagues discovered that the fibroinflammatory 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.

"That's the primary reason pancreas cancers are resistant to everything we've thrown at them: because none of the drugs get into the tumor. It's physics first, before we even get to the intrinsic biology," Hingorani said.

PEGPH20 is a PEGylated form of rHuPH20 modified to allow it to survive in the blood stream.  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.

"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," Hingorani said.

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The similar study is ongoing at Cancer Research UK's Cambridge Research Institute, confirming the possible abilities of the enzyme PEGPH20 to stretch open the insides of blood vessels in mice. Here, it was validated that greater amounts of two different chemotherapy drugs - gemcitabine and doxorubicin – were able to reach pancreatic tumors.

Study author, Professor David Tuveson, group leader at Cancer Research UK's Cambridge Research Institute, said: "Adding this enzyme to treatments could be a game-changer for treatment of pancreatic cancer if clinical trials show it can be used to treat patients safely. It made the shape of blood vessels wider and rounder - essentially it's the difference between changing the shape of blood vessels from a flat bicycle tire to a pumped up one. This allowed drugs to easily travel to the tumor and destroy it, when previously this was incredibly difficult. Also, the expanded blood vessels now have holes that allow the drugs to reach the tumor more effectively."

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A formulation of the PEGPH20 enzyme has already been approved by U.S. regulators for a different drug-delivery application. It is injected under the skin to form a pocket that helps fluids and standard drugs reach blood vessels. And a trial to test the PEGPH20-gemcitabine combination in pancreatic cancer patients is already under way. Although other tissues in the body contain HA, the enzyme doesn't seem to result in serious side effects in animal studies, says Hingorani, who is working on the trial being run by Halozyme Therapeutics (phase 2) from October 2011. He says if the treatment is successful, other potential drugs for PDA that had been shelved should be reexamined: "Maybe not enough of the drug got into the tumor," he says.

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