Treatment With Losartan May Improve Delivery of Chemotherapy Drugs in Tumors
Use of existing, well-established hypertension drugs could improve the outcome of cancer chemotherapy by opening up collapsed blood vessels in solid tumors. In a report published in Nature Communications, investigators from Massachusetts General Hospital (MGH) described how the angiotensin inhibitor losartan improved the delivery of chemotherapy drugs and oxygen throughout tumors by increasing blood flow in mouse models of breast and pancreatic cancer. A clinical trial based on the findings of this study is now underway.
Study Details
"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 Rakesh K. Jain, PhD, Director of the Steele Laboratory for Tumor Biology at MGH and senior author of the study. "Unlike antiangiogenesis 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 the physical and physiologic properties of tumors can inhibit cancer therapies, Dr. Jain's team previously found that losartan improves the distribution of nanomedicines within tumors by inhibiting collagen formation. The current study looked at whether losartan and other drugs that block the action of angiotensin could release the elevated forces within tumors that compress and collapse internal blood vessels. These stresses are exerted when cancer-associated fibroblasts proliferate and produce increased levels of both collagen and a gel-like substance called hyaluronan.
Losartan/Chemotherapy Combination Delays Tumor Growth
The team's experiments in several mouse models showed that both collagen and hyaluronan are involved in the compression of blood vessels within tumors and that losartan inhibited production of both molecules by cancer-associated fibroblasts through reducing the activation and overall density of these cells. Compared with angiotensin-converting enzyme (ACE) inhibitors, which block angiotensin signaling in a different way, losartan and other angiotensin receptor blockers appeared to be 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 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," explained Dr. Jain. "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.”
Vikash P. Chauhan, PhD, and John D. Martin, both of Massachusetts General Hospital and Harvard Medical School, are co-lead authors of the Nature Communications report.
The study was supported primarily by National Cancer Institute grants and the Department of Defense Breast Cancer Research Program Innovator Award.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
