Overcoming Cancer Drug Failure

A recent study discovered that hyaluronic acid is responsible for elevated gel-fluid pressure in tumors, which sometimes causes cancer drugs to fail.

Researchers administered an enzyme that breaks down hyaluronic acid in mouse models, and found this was able to normalize fluid pressures and allow vessels to re-expand in tumors, according to the study published in Biophysical Journal.

"We show that the gel-fluid phase generates a primary mechanism of drug resistance in pancreas cancer," said senior study author Sunil Hingorani, MD, PhD. "This also means that it may be worth revisiting some of the many agents that have previously failed in pancreas cancer patients and make sure they are first getting into the tumor. Similarly, elevated pressures due to a gel-fluid phase may be present in many other solid tumor types, so it may be worth seeing to what extent drug delivery can be improved in those settings as well."

Researchers know that hyaluronic acid can consume water and create a gel-like fluid in joints and organs, so they hypothesized that a large immobile-fluid phase caused by hyaluronic acid could be causing high pressures in many solid tumors. The researchers used a piezoelectric pressure catheter transducer to capture free- and immobile-fluid pressures.

A pressure sensor was inserted in tumors in a mouse model of pancreatic cancer through a probe. Researchers also used the standard technique to perform this measurement, wick-in-needle. The fluid pressure measured by the piezoelectric pressure catheter transducer were higher than those captured by the wick-in-needle technique, the researchers found.

“Taken together, the findings show that the hyaluronic acid-dependent immobile fluid phase plays a previously underappreciated role in driving high pressures in solid tumors," Dr Hingorani said.

Then, researchers treated a mouse model of pancreatic cancer with a modified form of hyaluronidase, an enzyme that breaks down hyaluronic acid.

Researchers found this treatment is able to stop the immobile fluid phase to allow blood vessels to re-expand. Since collapsed vessels create a roadblock for drug delivery, researchers believe these findings indicate hyaluronidase treatment could be a promising way to treat drug-resistant cancers.

There are current clinical trials examining the safety and efficacy of hyaluronidase combination therapy. Researchers said that preliminary results show that the treatment improves response rates and progression-free survival.

According to the study, researchers plan to examine the mechanisms behind high immobile fluid pressures in solid tumors.

"Given the importance of immobile fluid in cancer resistance, additional insights into the underlying mechanisms will could inform the development of treatment strategies that are most likely to succeed," Dr Hingorani concluded.