In the war against cancer, doctors and patients have long reached for three main weapons to target diseased cells: Chemotherapy, radiation, and surgery.
But new research published this month in the journal Nature Materials suggests that manipulating the tissue around those cells — a strategy known as “mechanotherapeutics” — could play a critical role in reducing drug resistance and improving survival rates for hard-to-treat cancers like pancreatic cancer.
“Our study shows the importance of the tumor microenvironment and its properties in dictating how cancer progresses and responds to drug treatment,” said first author Bauer LeSavage, PhD, who conducted the study as a postdoctoral researcher in the Bioengineering Department at Stanford University, Stanford, California. “It also demonstrates that chemoresistance can be reversed.”
Each year, about 66,000 people are diagnosed with pancreatic cancer, and 52,000 die from it. It is a particularly lethal type of cancer, with 5-year survival rates hovering around 7% — a rate that has not improved much since 1996 when the first-line chemotherapy drug gemcitabine was approved.
It looks different from many cancers, said Lynn Matrisian, PhD, chief science officer for the nonprofit Pancreatic Cancer Action Network. Instead of a tumorous mass, it is made of islands of cancer cells surrounded by unusually dense fibrous tissue known as the extracellular matrix, which can collapse blood vessels and prevent drugs from reaching the tumor.
For the study, LeSavage and his team engineered synthetic but lifelike three-dimensional pancreas tissue with varying degrees of stiffness and different biochemical properties. Then they inserted bits of real tumors from patients with pancreatic cancer, watched them grow, and tried to kill them with drugs.
They found that cells growing in a stiff matrix were more resistant to chemotherapy than those growing in a softer matrix. But the story didn’t end there.
They also found that high amounts of the tissue-strengthening protein hyaluronic acid in stiff tissue seemed to signal the cancer cells to develop tiny pumps on their surface which shuttled out the drugs before they could take effect.
When the researchers moved the cancer cells into either a softer matrix or a stiff matrix in which the hyaluronic acid receptor, called CD44, was blocked, the chemotherapy drugs started working again.
“This suggests that if we can disrupt the stiffness signaling that’s happening through the CD44 receptor, we could make patients’ pancreatic cancer treatable again by normal chemotherapy,” said senior study author Sarah Heilshorn, PhD, a professor of materials science and engineering at Stanford. “These results suggest an exciting new direction for new drug development.”
Targeting Nearby Tissue: A Novel Approach to Fighting Chemoresistance
The study is not the first to suggest that chemically targeting the microenvironment surrounding a tumor can influence how patients respond to treatment.
In one recent clinical trial, patients with metastatic pancreatic cancer were given an experimental drug to inhibit a protein called connective tissue growth factor, reduce fibrous tissue, and make pancreatic tumors easier to surgically remove. Results have not been published yet.
Other research suggests that the generic blood pressure drug losartan, when given in combination with chemotherapy and radiation, can boost survival in patients with advanced pancreatic cancer by, in part, improving the health of blood vessels that carry drugs to the tumor.
But other studies of such mechanotherapeutics have yielded inconclusive results, said Matrisian.
“This paper points to another reason why we should not give up on this approach,” she said.
Ning Wang, PhD, director of the new Institute for Mechanobiology at Northeastern University College of Engineering, Boston, said there is no question that the composition of a tumor’s environment can influence how cancer progresses or responds to drugs. The new paper, he said, adds an important new chapter to the evolving story.
“But it’s very complicated. It’s not as simple as saying make it softer or stiffer and you can change the outcome for the patient,” Wang said.
In fact, some research has shown that tissue becomes stiffer when cancer arises so it can contain it from spreading.
In one animal study of pancreatic cancer that had spread to the liver, administering drugs to soften the surrounding tissue, or stroma, actually had the opposite effect — accelerating tumor growth and reducing survival rates.
Wang also noted that any drug designed to influence the extracellular matrix would need to be extremely localized, to prevent damage to other tissues, like bone or heart muscle.
LeSavage said he sees the paper as a case study in how important the extracellular matrix is and an example of how artificially grown organs or tissues can play a key role in testing how drugs work or don’t work.
He imagines a day when doctors could personalize treatments by taking a bit of a patient’s tumor, growing it in artificial tissue, and seeing how different tissue-altering drugs affect different therapies.
“This isn’t something that is just unique to pancreatic cancer,” he said, noting that the extracellular matrix throughout the body interacts with different cancers. “If we could take someone who has a chemo-resistant tumor and convert it into something that is sensitive to existing therapies again, we could give them a second chance.”
Source link : https://www.medscape.com/viewarticle/chemoresistance-can-be-reversed-toughest-cancers-targeted-2024a1000d7s?src=rss
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Publish date : 2024-07-18 11:18:34
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