A new study from a Massachusetts General Hospital (MGH) research team has found that the hypertension drug losartan, which targets the angiotensin signaling pathway, may improve the effectiveness of chemotherapy agents used to treat ovarian cancer. Previous research from the same team identified a similar effect for losartan in animal models of breast and pancreatic cancer, leading to a phase 2 clinical trial that had promising results against pancreatic cancer.
"We know that solid stress imposed by growing cancer cells and the extracellular matrix molecules they produce can compress blood vessels, reducing delivery of drugs and oxygen to tumors," says Lei Xu, PhD, of the Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology, co-senior author of the report published online in PNAS. "The extracellular matrix itself can keep high-molecular-weight drugs from penetrating tumors, and angiotensin signaling contributes to matrix formation. Since levels of an important enzyme in the angiotensin pathway are elevated and associated with poor outcomes in ovarian cancer, we investigated whether use of losartan to decrease fibrosis could improve outcomes in animal models of ovarian cancer."
In a series of experiments in two mouse models the investigators found the following:
- Losartan treatment reduced extracellular matrix content and solid stress in ovarian tumors, increasing blood supply, oxygen levels and drug delivery;
- A mathematical model based on tumor physiology predicts that adding losartan to both low- and high-molecular-weight cancer therapies, delivered either intravenously or intraperitoneally, could improve outcomes;
- Adding losartan to treatment with the chemotherapy drug paclitaxel enhanced the antitumor effect of intraperitoneal paclitaxel and also reduced the development of ascites, accumulations of fluid in the abdomen that significantly reduce patients' quality of life;
- Losartan depleted the extracellular matrix by inducing the expression of antifibrotic miRNA molecules, which could be used as biomarkers for response or resistance to chemotherapy;
An analysis of records of patients who received standard treatment for ovarian cancer at MGH or Brigham and Women's Hospital while also also being treated for hypertension found that those patients taking losartan or other angiotensin-targeting drugs at the time of diagnosis lived an average of 30 months longer than did those taking other hypertension drugs.
"The entire class of angiotensin-targeting drugs that includes losartan has been shown to reduce collagen accumulation in cardiac and renal fibrotic disease," says Xu, who is an assistant professor of Radiation Oncology at Harvard Medical School (HMS). "Losartan is a safe, and inexpensive drug that would cost less than $1/day while making a significant difference for patients with ovarian cancer."
Rakesh K. Jain, PhD, director of the Steele Labs, A.W. Cook Professor of Radiation Oncology at HMS and co-senior author of the PNAS report, adds, "Our findings - on top of the the beneficial results of the recent phase 2 trial for pancreatic cancer - should provide information and tools to explore a new therapeutic target for ovarian cancer, which leads to the death of around 14,000 women in the U.S. each year."
Study co-authors Olapado Yeku, MD, PhD, and David Spriggs, MD, of the MGH Gynecologic Cancer Program, hope to initiate a clinical trial of losartan in ovarian cancer patients later this year to test this strategy.
Support for the current study includes American Cancer Society Research Scholar Award RSG-12-199-01-TBG, National Cancer Institute (NCI) grants P01-CA190174 and U01-CA224348, NCI Outstanding Investigator Award R35-CA197743, and grants from the Jane's Trust Foundation, the Lustgarten Foundation, the Ludwig Center at Harvard, the National Foundation for Cancer Research and the Gates Foundation.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $900 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
Proceedings of the National Academy of Sciences