The five-year mortality rate for pancreatic cancer remains dismally low, despite numerous attempts to identify drugs more effective than standard gemcitabine. Now investigators from the Fred Hutchinson Cancer Research Center in Seattle and Translational Genomics Research Institute (TGen) in Phoenix think they’ve uncovered a biological reason for the lack of success –– and they think they’ve found a plausible solution.
The problem, they write in this week’s Cancer Cell, is that the extracellular matrix surrounding a pancreatic tumor squeezes the tumor to such a degree that the blood vessels collapse. In fact, the interstitial fluid pressure is so high in the tumor that it acts as a barrier for diffusion and prevents even small molecules from entering the tumor.
Instead of working with tissue culture cells or xenograft model, the investigators –– co-led by Daniel Von Hoff, MD, TGen's Physician-In-Chief, and Sunil Hingorani, MD, PhD, Associate Member of the Hutchinson Center's Clinical Research and Public Health Sciences –– used a strain of mice that more accurately reflects the genetics and histopathology of human pancreatic tumors.
When they measured the interstitial fluid pressure in normal pancreas and pancreatic tumors of anesthetized mice, they found a dramatic difference. The normal organ had an interstitial fluid pressure between 8 and 13 mm Hg; by contrast, the interstitial fluid pressure in tumors ranged from 75 to 130 mm Hg.
That pressure is enough to collapse the blood vessels and keep everything out.
Remarkably, they could reduce the intratumoral pressure by treating the mice with an enzyme that breaks down hyaluronic acid, a key component of the extracellular matrix. Shortly after treating the animals with the enzyme, called PEGPH20, the pressure dropped and blood vessels opened enough the researchers could discern vessel lumen in tumor sections.
And reducing the pressure, allowed gemcitabine to enter the tumor.
To demonstrate the value of reducing interstitial fluid pressure, the researchers conducted a randomized, placebo-controlled study in the mice comparing gemcitabine plus PEGPH20 and gemcitabine plus placebo.
Most of the mice treated with the combination showed objective tumor response while none of the ones treated with the control did. Moreover, the combination-treated animals lived significantly longer as well.
The combination is already being tested in patients in a phase 1b/2 trial, sponsored by the company developing PEGPH20.
The treatment appeared safe in mice, despite the fact that hyaluronic acid is found in a variety of organs, including the heart, lung, intestine, and liver. PEGPH20 treatment eliminated hyaluronic acid from these tissues with no apparent adverse effects on the animals. But safety in patients will have to be monitored.
Moreover, while the new approach may open the tumor to treatment in patients, the combination wasn’t sufficient to cure the mice. Therefore, getting the standard drug into tumors may be an important first step, but it is unlikely to be enough to cure patients.
Additional and more potent therapies will still be needed. The authors suggest the first place to look might be the drugs that failed in trials previously – this time though the drugs might actually be able to enter the tumor.
Dr. Von Hoff serves as a consultant for Halozyme Therapeutics, which is developing PEGPH20.