Losartan, an angiotensin inhibitor used to treat hypertension, may improve the delivery of chemotherapy drugs and oxygen to solid tumors, according to new research.
When cancer-associated fibroblasts proliferate, they produce increased levels of collagen and a gel-like substance called hyaluronan. Collagen and hyaluronan exert physical forces that compress tumor blood vessels, reducing vascular perfusion. A study published in Nature Communications (doi:10.1038/ncomms3516) examined whether losartan and similar drugs could decrease production of collagen and hyaluronan.
“Angiotensin inhibitors are safe blood pressure medications that have been used for over a decade in patients and could be repurposed for cancer treatment,” explained senior author Rakesh K. Jain, PhD, director of the Steele Laboratory for Tumor Biology at Massachusetts General Hospital (MGH) in Boston and Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School. “Unlike anti-angiogenesis drugs, which improve tumor blood flow by repairing the abnormal structure of tumor blood vessels, angiotensin inhibitors open up those vessels by releasing physical forces that are applied to tumor blood vessels when the gel-like matrix surrounding them expands with tumor growth.”
Jain’s group found that losartan inhibited production of collagen and hyaluronan by cancer-associated fibroblasts in mouse models of breast and pancreatic cancer. Losartan and other angiotensin receptor blockers were better at reducing compression of blood vessels within tumors than ACE inhibitors, which block angiotensin signaling in a different way. Treatment with losartan alone had little effect on tumor growth in animal models of breast and pancreatic cancer, but combining losartan with standard chemotherapy drugs delayed the growth of tumors and extended animal survival.
Jain said “Increasing tumor blood flow in the absence of anticancer drugs might actually accelerate tumor growth, but we believe that combining increased blood flow with chemotherapy, radiation therapy, or immunotherapy will have beneficial results.” Based on these findings in animal models, our colleagues at the MGH Cancer Center have initiated a clinical trial to test whether losartan can improve treatment outcomes in pancreatic cancer.” Information on this trial is available at http://clinicaltrials.gov/show/NCT01821729.