Cancer Drug May Overcome Physiological Resistance To Tuberculosis Medications

Rakesh K. Jain, Ph.D. A.W.Cook Professor of Tumor Biology Director, E.L. Steele Laboratory Department of Radiation Oncology Harvard Medical School and Massachusetts General Hospital Boston, MA Interview with:
Rakesh K. Jain, Ph.D.

A.W.Cook Professor of Tumor Biology
Director, E.L. Steele Laboratory
Department of Radiation Oncology
Harvard Medical School and
Massachusetts General Hospital Boston, MA    02114

Medical Research: What are the primary findings of this study and why are they important?

Dr. Jain: Pulmonary granulomas are the hallmark of the Tuberculosis (TB) infection, yet it is not fully understood how these structures contribute to disease progression and treatment resistance. In this study, we applied our insight in tumor biology – gained over three decades – to explore and exploit the similarities between vasculature (blood vessel network) in solid cancerous tumors and TB pulmonary granulomas. We demonstrate for the first time that TB granulomas have abnormal vasculature. This abnormality provides a mechanism for the observation that TB granulomas are often hypoxic (have low oxygen conditions) and have differential distribution of anti-TB drugs. We showed that bevacizumab, a widely prescribed anti-VEGF antibody for cancer and eye diseases, is able to create more structurally and functionally normal granuloma vasculature and improve small molecule delivery. This study suggests that vasculature normalization in combination with anti-TB drugs has the potential to enhance treatment in patients with TB.

Tuberculosis (TB) is a global scourge that is responsible for nearly 2 million deaths annually. Due to the inability of currently available treatment regimens to eradicate this devastating disease, it is clear that new treatment strategies are urgently needed. Unlike many researchers in the TB field, we do not seek to discover new therapeutics that target bacterial resistance; instead, we strive to overcome physiological resistance to treatment resulting from abnormalities in the granuloma vasculature that impair drug delivery and create hypoxia that impairs efficacy of drugs and immune system. By using an FDA-approved drug, our study has the potential to be rapidly translated into the clinic.

Medical Research: Has any association previously been made between the vascular structure of TB granulomas and the challenges of treating TB – both the fact that treatment takes so long and the development of multidrug resistance?

Dr. Jain: Our study is the first to implicate a specific facet of the granuloma – the abnormal vasculature – as a potential contributor to disease progression and treatment resistance. Granuloma hypoxia is known to negatively affect the local immune system while conferring resistance to some of the TB drugs. Our collaborators have shown that different anti-TB drugs have differential abilities to penetrate the granuloma structure, especially to the interior granuloma regions where the TB bacteria are found in greatest numbers. Our study is the first to provide evidence that by modulating the granuloma vasculature, hypoxia can be alleviated and drug delivery can be improved.

MedicalResearch: Did your group conduct any of the previous studies finding heterogenous drug distribution within granulomas? 

Dr. Jain: This is our first study that indicates heterogeneous distribution of a small molecule probe used as a drug surrogate, in tuberculosis granulomas. However, as mentioned above, our NIH collaborators in conjunction with researchers at Rutgers University have found differential distribution of several anti-TB drugs in the the granuloma using advanced mass spectrometry imaging and high-pressure liquid chromatography methods. Most notably, moxifloxacin is found concentrated in the granuloma’s cellular rim of macrophages and other cells outside the central necrotic zone and it is predominately excluded from the necrotic center of granulomas.

MedicalResearch: Did your group formulate the hypothesis that granulomas may have abnormal vasculature similar to that of solid tumors, which could interfere with drug delivery?

Dr. Jain: The ‘vascular normalization’ hypothesis was first introduced in 2001 by our group (Jain, Nature Medicine 2001). The hypothesis posits that rather than obliterating vessels, the judicious use of anti-angiogenic therapy can normalize the abnormal structure and function of tumor vasculature towards a more normal state. In turn, this normalizes the tumor microenvironment.   Over recent years, a large number of preclinical and some clinical cancer studies provided evidence in support of this hypothesis. Because of this, in 2009, Gates Foundation invited us to submit a research grant to investigate if our vessel normalization hypothesis can be applied to TB treatment. In this grant, we formulated the hypothesis.

MedicalResearch: What did your experiments show about granuloma vasculature and how it may affect drug delivery in your animal model?

Dr. Jain: In healthy tissues, blood vessels are able to supply oxygen, nutrients, and drugs that are administered with even distribution. We found in our study that granuloma vessels were structurally abnormal, and that this leads to poor vessel function. The poor functionality of abnormal blood vessels results in: 1) hypoxia, which can suppress the local immune cell function and compromises the efficacy of some anti-TB drugs, and 2) impaired delivery of anti-TB drugs to granuloma interior where the TB bacteria reside.

MedicalResearch: How do the abormalities of granuloma vasculature compare with those within solid tumors – both from a structural and functional standpoint?

Dr. Jain: The abnormalities of granuloma vasculature are very similar to tumor vasculature, both structurally and functionally. First, as in solid tumor, we found TB granulomas, from patient samples and from an animal model, overexpression VEGF, the main angiogenic factor that trigger the formation of new vessels. Second, we found the granuloma vessels are structurally abnormal, lacking pericytes that support the endothelial layer of the vessel wall. Third, granuloma vessels are functionally abnormal, with poor perfusion and impaired delivery of oxygen and small molecular weight molecules.

MedicalResearch: How did bevacizumab change delivery of the small-molecule dye in the animal model?

Dr. Jain: We found that bevacizumab treatment recruited more pericytes to the vasculature, which support the endothelial surface of blood vessel walls, this more structurally normal and mature granuloma vasculature, lead to improved perfusion. As a result, we observed that 3 days after bevacizumab treatment, delivery of a small molecule – used as a surrogate for TB-drugs – to TB lesions significantly increased.

MedicalResearch: The paper mentions that the transience of the normalization window of opportunity is also seen in cancer treatment.  In those instances, can anti-VEGF treatment be repeated to coincide with administration of chemo- or radiation therapy?  Could repeat treatment also be used in TB?

Dr. Jain: Several landmark clinical studies have now reported that combining bevacizumab with chemotherapy results in improved response. In these studies, standard concurrent chemoradiation was given in combination with periodic bevacizumab injections (every 2 or 3 weeks because of the long half-life of bevacizumab). Our experience in cancer suggests that anti-angiogenic treatment will need to be repeated in TB, however, the optimal treatment regimen for TB requires further investigation.

MedicalResearch: What could be the results – both for individual patients and for the global fight against TB – of improving the delivery of anti-TB drugs through vessel normalization by anti-VEGF treatment?

Dr. Jain: In cancer, vascular normalization can be combined with chemotherapies to improve the delivery and efficacy of anti-tumor drugs to the tumor. Similarly, we propose that combining vascular normalization drugs with anti-TB agents will result in improved drug delivery to the granuloma, and therefore, enhanced therapeutic outcome. By using an FDA-approved agent, our study has the potential to be rapidly translated into the clinic. Our hypothesis is that drug delivery and efficacy will be enhanced in patients, leading to shorter treatment regimens and reduced chances of reactivation/transmission.

MedicalResearch: What needs to be investigated next?

Dr. Jain: The next step is to combine our anti-VEGF agent, bevacizumab, with anti-TB drugs to assess any benefits to efficacy in our animal studies. This will confirm the clinical viability of such a therapeutic combination of drugs.


Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery
Meenal Datta, Laura E. Via, Walid S. Kamoun, Chong Liu, Wei Chen, Giorgio Seano, Danielle M. Weiner, Daniel Schimel, Kathleen England, John D. Martin, Xing Gao, Lei Xu, Clifton E. Barry III, and Rakesh K. Jain

PNAS 2015 ; published ahead of print January 26, 2015, doi:10.1073/pnas.1424563112 Interview with: Clifton E. Barry III, & Rakesh K. Jain, Ph.D. (2015). Cancer Drug May Overcome Physiological Resistance To Tuberculosis Medications