A new study reveals that a common class of drug used to control high blood pressure could enhance cancer treatment by improving delivery of chemotherapy drugs and oxygen through tumors. A clinical trial is already in progress as a result of the study.
Writing about their work in the online journal Nature Communications, researchers from Massachusetts General Hospital (MGH), an affiliate of Harvard Medical School, describe how the angiotensin inhibitor losartan increased blood flow and improved chemotherapy drug outcomes in mice with breast and pancreatic cancer.
Senior author Dr. Rakesh K. Jain, director of the Steele Laboratory for Tumor Biology at MGH, says:
“Angiotensin inhibitors are safe blood pressure medications that have been used for over a decade in patients and could be repurposed for cancer treatment.”
A class of drug called anti-angiogenesis drugs is already being used to improve blood flow through tumors to enhance cancer treatment.
But Dr. Jain points out that those drugs work by repairing the abnormal structure of tumor blood vessels, whereas angiotensin inhibitors open collapsed blood vessels: they release the physical forces that compress tumor blood vessels when the gel-like matrix that surrounds them expands as the tumor grows.
For their study, the researchers focused on how the structure and biology of tumors can impede cancer treatment.
In a previous piece of work, they had already discovered that by stopping the formation of collagen, a main constituent of the extracellular matrix, losartan helps distribute nanomedicines in tumors.
Reducing cancer-associated fibroblasts
In this new study, they wanted to find out if losartan and other angiotensin inhibitors could decompress collapsed blood vessels in tumors.
The blood vessels collapse under the forces exerted when certain tumor cells called cancer-associated fibroblasts (CAFs) begin to multiply and produce extra collagen and a gel-like substance called hyaluronan.
Using lab mice, the team showed that both collagen and hyaluronan play a part in the compression of blood vessels inside tumors, but losartan stopped production of both of them by reducing CAFs.
Losartan belongs to a class of drug called angiotensin receptor blockers, which work in a different way to another group known as angiotensin-converting enzyme (ACE) inhibitors.
The team suggests angiotensin receptor blockers are more effective at reducing compression inside tumors.
When they used losartan on its own to treat mice with breast and pancreatic cancer, there was no effect on tumor growth.
But when they combined losartan with standard chemo drugs, they delayed tumor growth and the mice lived longer.
Dr. Jain says if you improve blood flow in tumors without the chemotherapy drugs, you risk actually speeding up tumor growth.
But if you combine the increased blood flow with chemotherapy or other anti-cancer therapy, such as radiotherapy or immunotherapy, then you stand a better chance of slowing the tumor, he adds.
As a result of this study, the MGH Cancer Center has already started a clinical trial to find out if losartan can improve treatment results in pancreatic cancer.
Grants from the National Cancer Institute and a research program award from the Department of Defense helped to fund the study. Both MGH and a private company co-founded by Dr. Jain have applied for a patent based on the work behind the study.
In another study published recently, researchers from Ireland found that ACE inhibitors may slow dementia decline.