Common blood-pressure drugs could potentially improve the effectiveness of cancer chemotherapy if the outcomes seen in animal experiments hold true in people, HMS researchers at Massachusetts General Hospital report October 1 in the online journal Nature Communications.
By opening up collapsed blood vessels in solid tumors, the angiotensin inhibitor losartan improved the delivery of chemotherapy drugs and oxygen by increasing blood flow. Based on these findings in mouse models of breast and pancreatic cancer, a clinical trial is now under way.
“Angiotensin inhibitors are safe blood-pressure medications that have been used for over a decade in patients and could be repurposed for cancer treatment,” said Rakesh Jain, the Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School and senior author of the study. “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.”
Focusing on how tumors can inhibit cancer therapies, Jain’s team previously found that losartan improves the distribution within tumors of relatively large molecules called nanomedicines. The drug does this by inhibiting the formation of collagen, a primary constituent of the extracellular matrix.
The current study looked at whether losartan and other hypertension drugs that block the action of angiotensin—a hormone with many functions in the body—could release the elevated forces within tumors that compress and collapse internal blood vessels. These stresses are exerted when specialized cells in the tumor microenvironment called cancer-associated fibroblasts proliferate and produce increased levels of both collagen and a gel-like substance called hyaluronan.
The team’s experiments in several mouse models of cancer showed that both collagen and hyaluronan are involved in the compression of blood vessels within tumors. They also found that losartan inhibited production of both molecules by cancer-associated fibroblasts by reducing the cells’ activation and overall density.
Compared with blood-pressure drugs called ACE inhibitors, which block angiotensin signaling in a different way, losartan, and other angiotensin receptor blockers in its class, appeared better at reducing compression within tumors. In models of breast and pancreatic cancer, treatment with losartan alone had little effect on tumor growth, but combining losartan with standard chemotherapy drugs delayed the growth of tumors and extended survival.
“Increasing tumor blood flow in the absence of anti-cancer drugs might actually accelerate tumor growth, but we believe that combining increased blood flow with chemotherapy, radiation therapy or immunotherapy will have beneficial results,” explained Jain, who is director of the Steele Laboratory for Tumor Biology at Mass General. “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.
The study was supported primarily by National Cancer Institute grants P01-CA080124, R01-CA126642, R01-CA085140, R01-CA115767 and R01-CA098706, and by Department of Defense Breast Cancer Research Program Innovator Award W81XWH-10-1-0016. Mass General and Xtuit Pharmaceuticals, a company co-founded by Jain, have applied for a patent based on the work described in this paper.
Adapted from a Massachusetts General Hospital news release.
