Charged with analyzing the similarities between granulomas and tumors, Meenal Datta discovered that both are structurally and functionally abnormal.
In 2015, she and other researchers looked at the vascular structures of granulomas and showed that they are compromised and leaky just like tumor blood vessels, which limits drug delivery and successful treatment in both diseases.
Now a study from the same team at the University of Notre Dame, Massachusetts General Hospital and the National Institutes of Health has identified a combination of medications that may improve blood flow within granulomas, benefiting drug delivery. Published in the Proceedings of the National Academy of Sciences, the study leverages decades of cancer research to study tuberculosis-affected lung tissue and improve treatment.
“Much like in tumors, many of the blood vessels in granulomas are compressed or squeezed shut — just like if you stepped on your garden hose,” said Datta, the first author on the study. “In cancer, we know that happens because of the growing tumor mass and the supportive protein scaffolding it puts down, called matrix. We thought maybe the same thing was happening in tuberculosis.”
The study confirmed that a similar phenomenon is occurring in granulomas — too much cell mass and protein scaffolding. This impaired function makes blood flow through blood vessels nearly impossible, crippling the ability to get a medication to the tuberculosis disease site.
Datta and her collaborators used losartan, an affordable drug used to treat high blood pressure. However, it also has the beneficial side effect of reducing the amount of matrix being created inside a granuloma, thus opening the compressed blood vessels and restoring blood flow.
Researchers then combined losartan with bevacizumab, a drug used by cancer patients to stop the overproduction of poorly formed blood vessels. With this two-pronged medicinal approach, Datta and the team were able to make the granuloma blood vessels function and behave more normally.
When the researchers applied the host-directed therapies losartan and bevacizumab along with antibiotics, they showed improved drug delivery and antibiotic concentration within granulomas.
Additionally, Datta’s graduate student Maksym Zarodniuk analyzed genome sequencing data produced by the team, and found that even without antibiotics, there was a reduction in tuberculosis bacteria within the granulomas.
