A promising new cancer therapy appears to be highly potent against one of the world’s most devastating infectious diseases: tuberculosis (TB).
Scientists at the Texas Biomedical Research Institute (Texas BioMed) have discovered that the therapy dramatically reduces the growth of tuberculosis, even for bacteria that are drug-resistant. Results, reported in journal Biomedicine and PharmacotherapyDeveloped novel cellular models involving TB-infected human cells that may help accelerate the screening of potential TB drugs and such therapies.
The therapy evaluated in this study combines two molecules – one of which is already FDA-approved for use in cancer patients, and the other which is being evaluated in phase 1/2 clinical trials for cancer. The compounds help the body initiate its normal cell death process in the targeted area, be it cancer cells or, in this case, infected cells. which is Mycobacterium tuberculosis (M.tb), bacteria that cause TB.
TB is responsible for more than 1.6 million deaths worldwide each year. Bacteria primarily infect the lungs. Patients may take several months of antibiotics to control active infections; Drug resistance is increasing, making treatment more challenging.
Dr. Schlesinger’s lab at Texas Biomed focuses on understanding the fundamental biological interactions between airborne-infectious bacteria and humans, and then using those insights to identify potential therapeutic targets.
M.tb Blocks a normal cell death process called apoptosis. This allows the bacteria to grow inside the immune cells of the lungs, called alveolar macrophages. This new paper shows that by inhibiting two key proteins, MCL-1 and BCL-2, M.tb can no longer hijack the apoptosis process and kill macrophages M.tb.
Importantly, it occurs within granuloma structures, the dense cellular clumps that form around the body M.tb To try to contain it. Granulomas have a notoriously difficult time penetrating antibiotics and other treatments, which is one reason M.tb So hard to eradicate.
Immunotherapy has become a game changer in cancer by finding ways to help a patient’s own immune system fight tumors more effectively. We believe that, similarly, host-directed therapies could be a gamechanger for infectious diseases.”
Larry Schlesinger, MD, Texas Biomed professor, president and CEO and senior paper author
The research team, led by Texas BioMed staff scientist Eusondia Arnett, PhD, tested MCL-1 and BCL-2 inhibitors separately in combination with TB antibiotics to see how TB growth was affected. Using both inhibitors was more effective than one or the other in limiting TB growth; And combining them with antibiotics was much more effective than either the inhibitor or the antibiotic alone.
“Inhibitors combined with antibiotics control up to 98% of TB, which is very exciting,” said Dr. Arnett, author of the first paper. “But even more exciting is that the inhibitors were just as effective in controlling drug-resistant TB as they were in drug-susceptible TB. This is the strength of a host-directed therapy that tries to target the human immune system and attack the pathogen directly.”
A key aspect of the research is the cellular models used to test the efficacy of the inhibitors: human macrophages and a human granuloma model. Schlesinger’s lab for the past decade. Human blood cells donated by volunteers are cultured M.tbwhich leads to the formation of granuloma-like structures.
“Granulomas are unique, dense environments that don’t replicate well in mice,” Dr. Arnett said. “Our studies show 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 the necessary – but more complex, time-consuming and expensive – animal research phase.”
Dr. Schlesinger and Dr. Arnett has filed a provisional patent for a combination therapy for infectious diseases. They plan additional cell, mouse, and nonhuman primate studies to gather more evidence about the therapy’s effectiveness and seek partnerships with industry collaborators. They are hopeful that the therapy can move to the clinic quickly because years of safety studies for the inhibitors for cancer applications have already been completed, or are underway.