How cancer becomes drug-resistant

A team of researchers, including an Indian-American scientist, has found that the major reason cancer drugs fail is that they cannot penetrate the high-pressure environment of solid tumours.

The findings revealed that hyaluronic acid -- a large, naturally occurring molecule -- is primarily responsible for generating elevated gel-fluid pressures in tumours.

"We show that the gel-fluid phase generates a primary mechanism of drug resistance in pancreas cancer," said lead researcher Sunil Hingorani from the Fred Hutchinson Cancer Research Center in the US.

A hyaluronidase treatment -- family of enzymes that degrade hyaluronic acid -- holds promise for improving patient outcomes for drug-resistant cancers.

In the study, published in Biophysical Journal, the team conducted hyaluronidase treatment in a mouse model of pancreatic cancer and found that it broke down hyaluronic acid as well as normalised the fluid pressure in tumours, allowing vessels to re-expand and thereby overcoming a major barrier to drug delivery.

This treatment eliminated the immobile fluid phase and allowed vessels that had collapsed under pressure to re-expand. Preliminary results have shown that this treatment significantly improves response rates and progression-free survival in pancreatic cancer patients.

Using an instrument called piezoelectric pressure catheter transducer, the team captured both free- and immobile-fluid pressures in tumours.
The measurements of fluid pressure using the new instrument were much higher.

Moreover, elevated fluid pressures measured by the instrument correlated with high levels of hyaluronic acid in a variety of tumour models. "The findings show that the hyaluronic acid-dependent immobile fluid phase plays a previously underappreciated role in driving high pressures in solid tumours," Hingorani added.

The researchers plan to further examine the mechanisms behind high immobile fluid pressures in solid tumours. "Similarly, elevated pressures due to a gel-fluid phase may be present in many other solid tumour types, so it may be worth seeing to what extent drug delivery can be improved in those settings as well," Hingorani noted.