Do Cancer Drugs Hold the Answer to TB Treatment?
Author:
Eusondia Arnett, PhD
Texas Biomedical Research Institute
Citation:
Arnett E. Do cancer drugs hold the answer to TB treatment? [published online April 9, 2019]. Pulmonology Consultant.
I am in Dr Schlesinger’s lab, and we are interested in understanding why tuberculosis (TB) is still a leading cause of death worldwide. We also want to help expand treatment options to complement the currently available antibiotics with host-directed therapy to bolster the immune system. By doing this, drug-resistant TB can be treated, and it should be harder for the bacteria to become resistant to those drugs.
To reach this goal, we study how Mycobacterium tuberculosis interacts with the host immune system. For example, we study macrophages, which control and kill pathogens. However, M tuberculosis resides and grows within these macrophages during infection. Apoptosis is a type of cell death used by the host to limit M tuberculosis infection, and it has been known for some time that M tuberculosis can suppress apoptosis to help it propagate inside the host. We have characterized a new pathway explaining how M tuberculosis can inhibit apoptosis. In doing so, we have found that this occurs through proteins (including MCL1) that are also implicated in some cancers.
This knowledge is expected to influence the development of treatment options for M tuberculosis infection, especially in light of antibiotic resistance. Because of the link to cancer, we were able to repurpose several cancer therapeutics and found that they limit M tuberculosis growth inside macrophages by 80%. These are exciting findings for us and provide a great target in MCL1 for host-directed therapy.
Some of the drugs we have been testing have other drugs in the same family that are already in phase II clinical trials for treatment of cancer, we are starting to test those in our model system to see if they will also help limit M tuberculosis growth. Doing this will help make the transition to the clinic that much quicker, because the drugs have already gone through some of these required clinical trials.
Role of Granulomas in This Research >>
The Role of Granulomas
Granulomas are multi-cellular complexes of immune cells, so they contain macrophages that are used by the host to try to control M tuberculosis growth. However, they are dense structures so it is hard for antibiotics to penetrate granuloma structures; that is part of why treatment for TB takes so long. Short-course treatment for TB is at least 6 months.
We have been able to study and model these granulomas on the bench and have found that these anti-cancer drugs that reduce M tuberculosis growth in macrophages also reduce M tuberculosis growth in granuloma structures. This is promising and suggests that these drugs can also be active in animals, which would be the next step, to see if we can use these drugs to help control TB in mice before translating this to the clinic for people with TB.
Cancer Drugs and M. tuberculosis
Regulation of cell death is critical for general health. This importance is exhibited through cancerous cells, which do not properly regulate cell death—they do not undergo apoptosis like they should, and so they develop into tumors. Cell death is also altered during TB, and apoptosis can be used to limit M tuberculosis growth; so if we can find a way to induce apoptosis during infection, we expect that we can then control and limit M. tuberculosis growth.
We found that M tuberculosis induced MCL1, a protein that is important for dampening apoptosis. By studying this, we were able to better understand how M tuberculosis can regulate macrophage death and inhibit apoptosis. MCL1 has been heavily studied in other cancer cells, because it is highly expressed in various cancers, and so identifying this allowed us to identify a host-directed target that can be used to treat TB as well as various cancers.
There is still a lot to understand about how TB affects macrophages and granuloma structures. That is really what we are interested in studying: trying to identify other host targets that might be druggable to help control this organism so that we can really start to limit and better treat tuberculosis.
Eusondia Arnett, PhD, is a staff scientist II in Larry Schlesinger's Laboratory at Texas Biomedical Research Institute in San Antonio, Texas.
This commentary is a transcription of an interview with Dr Arnett. Listen to the whole podcast at https://www.consultant360.com/podcast/infectious-diseases/dr-eusondia-arnett-apoptosis-m-tuberculosis-infection.
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