Resistance to Cancer Drugs Can Be Reversed – Targeting the Toughest Cancers

In cancer treatment, doctors and patients have long relied on three main methods to target diseased cells: chemotherapy, radiation, and surgery.

However, a new study published on July 4, 2024, in Nature Materials suggests that manipulating the tissue surrounding these cells—a strategy known as "mechanotherapeutics"—could play a crucial role in reducing drug resistance and in pancreatic cancer and other difficult-to-treat cancers by improving survival rates.

Cancer's Shield: The Tumor Microenvironment

The study's first author, Bauer LeSavage, a postdoctoral researcher in Stanford University's Department of Bioengineering, says: "Our study demonstrates the importance of the tumor microenvironment and its properties in determining how cancer progresses and responds to drug treatment. It also shows that chemical resistance—that is, resistance to cancer drugs—can be reversed."

The 5-year survival rate for pancreatic cancer is around 7%, and it has changed little since the first-line chemotherapy drug gemcitabine was approved in 1996.

Pancreatic cancer looks different from many other cancers. Rather than a tumor mass, it consists of islands of cancer cells surrounded by exceptionally dense fibrous tissue, known as the extracellular matrix. This tissue can distort the structure of tumor-associated blood vessels and prevent drugs from reaching the tumor.

For the study, LeSavage and his team engineered synthetic but realistic three-dimensional pancreatic tissue with varying stiffness and biochemical properties. They then implanted actual tumor fragments from patients with pancreatic cancer into these tissues, monitored their growth, 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 soft matrix. But the story did not end there.

They also found that a tissue-strengthening protein called hyaluronic acid, present at high levels in stiff tissues, signals cancer cells to develop small pumps on their surfaces that expel drugs before they can act.

The Key to Stiff Tissues: Overcoming Chemical Resistance Through the CD44 Receptor

The researchers examined the effects of drugs by changing the stiffness of the tissue surrounding cancer cells. They tested two different conditions:

1. Soft Tissue: When they moved cancer cells into softer tissue, they found that chemotherapy drugs became effective against these cells again.

2. Blocking the CD44 Receptor: When they blocked the hyaluronic acid receptor (CD44), which is present in stiff tissue and helps cells pump drugs out, they again observed that chemotherapy drugs were effective.

In other words, reducing the stiffness of the tissue surrounding the cells or blocking the CD44 receptor that causes cells to develop drug resistance increased chemotherapy drugs' ability to destroy cancer cells. This could open a new path for treating chemotherapy-resistant cancers.

Another author of the study, Sarah Heilshorn, a professor of materials science and engineering at Stanford University, says: "This suggests that if we can disrupt the stiffness signal transmitted through the CD44 receptor, we could make patients' pancreatic cancers treatable with conventional chemotherapy again. These results point to an exciting direction for new drug development."

Targeting Nearby Tissues: A New Approach to Combating Chemical Resistance

This is not the first study to suggest that chemically targeting the microenvironment surrounding a tumor could influence how patients respond to treatment.

In a clinical trial, patients with metastatic pancreatic cancer received an experimental drug intended to inhibit a protein called connective tissue growth factor, reduce fibrous tissue, and make pancreatic tumors surgically removable. The results have not yet been published.

Another study suggests that losartan, a common blood pressure medication, may improve survival in patients with advanced pancreatic cancer when given with chemotherapy and radiotherapy, in part by improving the health of blood vessels that deliver drugs to the tumor.

The Challenges and Future Potential of Mechanotherapeutics

It is important to recognize that other studies of these mechanotherapeutic approaches have produced conflicting results.

There is no doubt that the composition of the tissue surrounding a cancer can influence how the disease progresses or responds to drugs. However, the process is highly complex. It is not as simple as saying that tissue needs to be softened or stiffened to change a patient's treatment outcome.

Some studies have shown that tissue stiffens when cancer develops, thereby preventing its spread. For example, in an animal study of pancreatic cancer that had spread to the liver, drugs given to soften the surrounding tissue accelerated tumor growth and reduced survival rates.

Any drug designed to affect the extracellular matrix must be extremely localized so that it does not damage other tissues, such as bone or heart muscle.

Artificially grown organs or tissues may play an important role in testing how drugs work—or fail to work. In the future, doctors may be able to take a piece of a patient's tumor, grow it in artificial tissue, and see how different tissue-modifying drugs affect different therapies. This could revolutionize the personalization of treatment.

This approach is not unique to pancreatic cancer. The extracellular matrix throughout the body interacts with different cancers. If we can take a patient with a chemically resistant tumor and make that tumor sensitive to existing treatments, we can give patients a second chance.