SAN ANTONIO, Nov. 16, 2023 /PRNewswire/ — A promising new cancer therapy also appears extremely potent against one of the world’s most devastating infectious diseases: tuberculosis (TB).
“We believe that host-directed therapies can be a game changer for infectious diseases.” – Larry Schlesinger, MD
Scientists at Texas Biomedical Research Institute (Texas Biomed) found the therapy dramatically reduces TB growth, even for bacteria that are drug-resistant. The findings, reported in the journal Biomedicine & Pharmacotherapy, were made in novel cellular models that can help accelerate screening of potential TB drugs and therapies like this one.
The therapy evaluated in this study combines two molecules – one is already FDA-approved for cancer patients, and the other is in Phase 1/2 clinical trials for cancer. The compounds help the body initiate its normal cell death processes in targeted areas, be it cancerous cells, or in this case, cells infected with Mycobacterium tuberculosis (M.tb), the bacteria that causes TB.
“Immunotherapy has been a game changer in the cancer field by finding ways to help a patient’s own immune system fight tumors more effectively,” says Larry Schlesinger, MD, Texas Biomed Professor, President and CEO. “We believe that, similarly, host-directed therapies can be a game changer for infectious diseases.”
TB causes more than 1.6 million deaths worldwide every year. The bacterium primarily infects the lungs. Patients must take antibiotics for months to bring active infection under control; drug resistance is on the rise, making treatment even more challenging.
Dr. Schlesinger’s lab seeks to understand the fundamental biological interactions between the bacteria and humans, and use those insights to identify potential treatment targets.
M.tb blocks a normal cell death process called apoptosis. This allows the bacteria to grow inside immune cells in the lungs, called alveolar macrophages. The scientists found that by inhibiting two key proteins, MCL-1 and BCL-2, M.tb can no longer hijack the apoptosis process and macrophages are able to kill M.tb.
Importantly, this happens inside granuloma structures, the dense cellular clumps the body forms around M.tb to try to contain it. Antibiotics have a notoriously difficult time penetrating granulomas, which is one reason why M.tb is so hard to eliminate.
The research team, led by Texas Biomed Staff Scientist Eusondia Arnett, PhD, tested MCL-1 and BCL-2 inhibitors individually, together and in combination with TB antibiotics to see how TB growth was affected. Using both inhibitors was more effective at limiting TB growth than just one or the other; and combining them with antibiotics was far more effective than either inhibitors or antibiotics alone.
“The inhibitors combined with antibiotics controlled TB up to 98%, which is very exciting,” says Dr. Arnett. “But even more exciting is the inhibitors were just as effective at controlling drug-resistant TB as drug-susceptible TB. That’s the power of a host-directed therapy targeting the human’s immune response versus trying to attack the pathogen directly.”
A key aspect of the research are the cellular models used to test the inhibitors: human macrophages and a human granuloma model developed and refined in Dr. Schlesinger’s lab over the past decade. Human blood cells donated by volunteers are cultured with M.tb, which leads to the formation of granuloma-like structures.
“Granulomas are unique, dense environments that are not well replicated in mice,” Dr. Arnett says. “Our studies demonstrate that this cellular model can serve as an important bridge to identify compounds that can penetrate and retain activity in granulomas, before we move to more complex, time-consuming and expensive research phases.”
Texas Biomed is a nonprofit research institute focused on infectious diseases. Through basic research, preclinical testing and innovative partnerships, Texas Biomed accelerates diagnostics, therapies and vaccines for the world’s deadliest pathogens.
SOURCE Texas Biomedical Research Institute
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