Scientists Unlock Mystery of What Makes Cancer Chemotherapy-Resistant

A team of researchers has discovered a major reason why many cancer drugs fail, the source of this problem, and how to prevent it.

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The scientists found out that one of the reasons pancreatic tumours are enormously hard to treat is that they are filled with so much pressure that blood vessels collapse and cancer-fighting drugs can’t enter  cells.The study revealed that hyaluronic acid, a naturally occurring molecule, is responsible for generating gel from free-flowing fluid, putting the squeeze on tumours. Pancreatic cancers produce this acid in very high amounts, and it traps even more water to create a gel, until it jams blood vessels shut and blocks chemotherapy.

Pancreatic tumours are notoriously hard to treat; one of the reasons is they are filled with so much pressure that blood vessels collapse and cancer-fighting drugs can’t get in. But now Fred Hutch researchers Drs. Sunil Hingorani and Christopher DuFort have a better understanding of exactly what causes the pressure – and what might be done to lessen it.

Internal pressure makes pancreatic tumours hard to treat
The blood vessel-crushing, chemo-blocking pressure inside pancreatic tumours is almost entirely due to water trapped in gel form, a new study shows. FREDHUTCH.ORG

The team of researchers led by Dr. Sunil Hingorani, an Indian-American oncologist from the Fred Hutchinson Cancer Research Center in the US, used a special instrument known as a piezoelectric catheter to take a deeper dive into pancreatic tumours. Unlike older, more commonly used instruments, tool was able to detect pressure in tumours that is usually overlooked. To the researchers’ surprise, the machine registered the tumours as having internal pressure of up to 100 mmHg. “That’s equal to the pressure the heart uses to pump blood through the entire body. It’s definitely enough to collapse capillary blood vessels,” said the study’s first author Dr. Christopher DuFort, a post-doctoral researcher at Hingorani’s lab.

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Hingorani and his group also found a strategy to sufficiently relieve the pressure. The research showed that the use of a special agent, enzyme PEGPH20, helps to reduce pressures inside pancreatic tumours. The enzyme digests the hyaluronic acid and turns its gel back into free-flowing water, blood vessels open up, and drugs are carried in by the bloodstream. The combination of cancer drugs and this enzyme can double survival time for some pancreatic cancer patients, the researchers claim.

“We’ve described this in one specific example in the pancreas, but there are other tumor types that have high levels of this unique molecule [the hyaluronic acid]. So it could be warranted to look at this in other contexts as well,” said Dr. DuFort.

Nailing down the source of the high internal pressure of pancreatic tumours opens up many avenues — for research, and for optimism, concluded Dr. Hingorani.

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