Harvard University. US: Antiangiogenesis drugs could normalize blood vessels within TB lung lesions, increasing drug delivery and reducing resistance. The same antiangiogenesis drugs that have improved treatment of some
cancers could also help surmount persistent difficulties in treating
tuberculosis.
In their PNAS Early Edition report,
Harvard Medical School investigators from Massachusetts General
Hospital, working with colleagues at the National Institute of Allergy
and Infectious Diseases (NIAID), show that blood vessels supplying
pulmonary granulomas—dense masses of immune cells that surround pockets
of the TB bacteria in the lungs of infected patients—have the same sort
of structural and functional abnormalities seen in solid tumors.
Treatment with the antiangiogenesis drug bevacizumab (Avastin)
significantly improved delivery of a small-molecule drug surrogate
within granulomas in an animal model.
“By applying insights gained over three decades of work in tumor
biology, we have demonstrated for the first time that TB granulomas have
an abnormal blood vessel network that explains several observations
previously made by our NIAID coauthors,” said Rakesh Jain,
the HMS A. Werk Cook Professor of Radiation Oncology (Tumor Biology) at
Mass General. He is director of the Edwin L. Steele Laboratory for
Tumor Biology at Mass General and co-senior author of the PNAS Early Edition
paper. “Our findings that bevacizumab—an FDA-approved drug now widely
prescribed for cancer and eye disease—can normalize granuloma
vasculature and improve small-molecule delivery suggests that combining
such drugs with anti-TB drugs may enhance TB treatment and potentially
reduce the growing problem of antibiotic resistance.”
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While as many as one-third of the world's population may be infected
with the bacteria that causes TB, most people with the infection never
develop disease. Weakening of the immune system related to HIV
infection, chemotherapy or other causes can result in active TB disease,
in which bacteria proliferate and attack tissues in the lungs and
sometimes other organs. Treatment for TB involves a lengthy course of
multiple antibiotic drugs, typically four or more drugs for six to eight
months. A growing problem is the appearance of bacterial strains
resistant to the two primary antibiotics used to treat TB, with some
resistant to as many as 10 drugs, contributing to almost 2 million
deaths from TB every year worldwide.
Recent studies have explored structural features of TB granulomas in
humans and animals with active disease. The NIAID co-authors of the PNAS Early Edition report, led by co-senior author Clifton Barry,
chief of the Tuberculosis Research Section at NIAID, and others have
observed that the ability of anti-TB drugs to penetrate the lesions
varies widely, with few able to reach high concentrations within the
central zone of dying cells. Other aspects of the environment within
granulomas have been observed, including low levels of oxygen, which can
restrict the action of immune cells; but no previous study has
investigated the structure and function of granuloma blood vessels and
their effect on treatment of TB.
As described in the current study, the research team discovered
several similarities between the blood vessel networks of granulomas in a
rabbit model of TB and those of solid tumors. These included elevated
expression of the potent angiogenesis factor VEGF (vascular endothelial
growth factor), which was also seen in granulomas from human patients;
structural abnormalities, such as a lack of cells that support blood
vessel walls; and extremely uneven distribution of blood vessels in the
lesions, with many compressed or collapsed vessels and few in the
centers of the lesions. Intravenous administration of a fluorescent dye
molecule, similar in size to common anti-TB drugs, revealed functional
abnormalities of granuloma vessels that so limited the dye’s penetration
of the lesions that little or none reached the central region.
Treating the infected animals with bevacizumab, an antibody that
blocks VEGF, produced structural improvements in granuloma vessels:
increased diameter, more support cells and fewer ineffective, immature
vessels. These structurally normalized vessels also were functionally
improved, with significantly better delivery of the marker dye and fewer
oxygen-starved cells throughout the lesion. As is the case when
angiogenesis drugs are used in cancer treatment, these effects lasted
less than a week, but the researchers anticipate that periodic
bevacizumab administration could improve the effectiveness of anti-TB
drugs as it has with several chemotherapies. In addition to reducing the
length of TB therapy, removing physical barriers that keep all
administered drugs from reaching all bacteria within granulomas should
reduce the development of bacterial resistance.
“Unlike many TB researchers, we are not seeking to discover new ways
of combating bacterial resistance. Instead, we are striving to overcome
physiological resistance to treatment caused by these vascular
abnormalities,” said Jain. “And since we are using an FDA-approved drug,
our work has the potential to be rapidly translated into clinical
use.”
Co-lead author Laura Via of
the Tuberculosis Research Section at NIAID added, “Several scientists
who have reviewed our study have expressed interest in collaborating
with us on clinical trials, which will need to wait until we can confirm
the viability of combining anti-TB drugs with bevacizumab in animal
studies. Combining anti-TB drugs with agents that promote drug access
into the lesions has the potential of making the drugs we use now more
effective at the same concentrations, lessening the need for high-dose
therapy or extended treatment in those with extensive disease.”
Support for the study includes National Cancer Institute grant
P01CA080214 and grants from the Bill and Melinda Gates Foundation and
from the NIAID Intramural Research Program.
Adapted from a Mass General news release.