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Enzyme 'Melts' Cancer Drug Barrier

19 March 2012 2:09 pm
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Researchers may have found a new way to treat pancreatic tumors, one of the deadliest and most drug-resistant forms of cancer. Injecting mice with a molecule that melts the tough structure around the tumor allowed a standard chemotherapy drug to better penetrate and destroy cancer cells. The strategy is already being tested in people.

People diagnosed with the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDA), usually don't respond to chemotherapy and only live a few months. Some researchers suspect that one reason is that the pancreatic tumor cells are enmeshed in a tough, fibrous matrix of cells and molecules known as the stroma. This may create fluid pressure within the tumor that is much higher than in the tumor's blood vessels, making it hard for any cancer drugs to diffuse from the blood into the tumor. Adding to the challenge, PDA tumors already have few obvious blood vessels penetrating them.

Oncologist and cancer biologist Sunil Hingorani's group at the Fred Hutchinson Cancer Research Center in Seattle, Washington, and collaborators confirmed the extreme fluid pressures in PDA tumors by inserting a special probe into tumors in mice with the disease. The pressures were "astonishing," Hingorani says—80 to 120 millimeters (mm) of mercury, which is comparable to the pressure of blood being pumped within the heart.

Looking for a way to lower that pressure so that drugs can breach the barrier, Hingorani's group focused on a sugar molecule called hyaluronic acid (HA), which is abundant in the stroma of PDA tumors. The team treated the mice with an enzyme called PEGPH20, which degrades HA. The pressure in the tissue around the tumor began to drop and by 24 hours had reached about 20 mm of mercury, the level seen in normal pancreas tissue. When the researchers cut out the animals' tumors, they were soft and pink, unlike the hard, white tumors from animals that had not received the enzyme, Hingorani says. His team also found that blood vessels in the tumors that had been compressed and hard to see had sprung open.

The next step was to see if chemotherapy drugs would get into a tumor more easily after it was treated with the enzyme. And indeed, when mice with PDA tumors were injected with PEGPH20 and gemcitabine, the standard drug for pancreatic cancer, they lived 70% longer (a median of 92 days) than mice receiving gemcitabine alone and developed fewer metastases, the team reports today in Cancer Cell. That's the longest survival his group has seen in this animal model of pancreatic cancer, Hingorani says.

A formulation of the PEGPH20 enzyme has already been approved by U.S. regulators for a different drug-delivery application. (It's 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. 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.

The results seen in the mice are "exceedingly encouraging," particularly because the animals treated with the enzyme combo developed fewer metastatic tumors, says cancer biologist Dafna Bar-Sagi of New York University Langone Medical Center. However, she and others caution that the results seen in mice may not translate into people. A few years ago, Hingorani was part of a team that used a different drug to shrink the stroma of PDA tumors. That strategy seemed promising in mice but apparently hasn't worked in the clinic.

Cancer biologist Craig Logsdon of MD Anderson Cancer Center in Houston, Texas, cautions that drug-blocking role of the stroma itself is debatable—he was part of some recent imaging studies that found molecules that penetrated pancreatic tumors. Still, "the disease is so terrible and people are looking for new options," he says. "Let us hope that my analysis is incorrect that this really does improve therapy."

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