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Mayo Clinic Researchers Successfully Use Anticancer Drug To Fight Fatal Lung Disease, Idiopathic Pulmonary Fibrosis

Date:
November 16, 2004
Source:
Mayo Clinic
Summary:
Mayo Clinic researchers have identified a treatment for the fatal lung disease idiopathic pulmonary fibrosis (IPF). They found that the anti-cancer drug imatinib mesylate — commercially known as Gleevec and produced by Novartis Pharmaceuticals — can target a gene critical to controlling the disease process.

ROCHESTER, Minn. — Mayo Clinic researchers have identified a treatment for the fatal lung disease idiopathic pulmonary fibrosis (IPF). They found that the anti-cancer drug imatinib mesylate — commercially known as Gleevec and produced by Novartis Pharmaceuticals — can target a gene critical to controlling the disease process. Previously, there had been no treatment and patients usually did not survive beyond three years of diagnosis. Now the treatment is undergoing clinical trials at Mayo Clinic.

The Mayo Clinic researchers describe their investigation in laboratory mice in the current edition of the Journal of Clinical Investigation (http://www.jci.org). The gene they identified is known as c-Abl, and it initiates the destructive, abnormal growth of lung tissue. Moreover, the drug Gleevec inhibits c-Abl. Because Gleevec was already approved by the U.S. Food and Drug Administration for use in certain cancers, the researchers were able to speed the Gleevec treatment into human trials.

<b>Significance of the Mayo Clinic Research</b>

No one knows what causes idiopathic pulmonary fibrosis — and until now, no one has known how to alter its inexorable course. Most researchers have focused on the role of inflammation and physicians treated the disease with anti-inflammatory drugs — without encouraging results. By taking a new focus away from inflammation to examine the biochemical signaling events and genes involved, the Mayo Clinic group became the first to arrive at a practical solution to benefit patients.

“I treat patients with this disease, and to have to tell someone they have this lethal disease and that there’s no treatment for it is just devastating for them,” says first author Craig Daniels, M.D. “Even though these are animal studies and the results still need to be investigated in humans, we certainly know more now than we did a few years ago, or even a year ago, and this tells me we eventually will find a standard treatment for IPF. That’s the best part. That will be one of the happiest days of my life when that’s true.”

“The nice thing about this study is that it shows that since TGF Beta and PDGF are two of the most pro-fibrotic growth factors known — and Gleevec inhibits the action of both — one treatment works on multiple targets,” says Edward Leof, Ph.D., senior author and principal investigator of the preclinical study. “And because TGF Beta and PDGF are such strong and widespread pro-fibrotic growth factors, our findings suggest that many fibrotic diseases will likely be impacted by this, not just pulmonary fibrosis — kidney fibrosis, for example, and fibrotic cancer tumors.”

Andrew Limper, M.D., is a Mayo Clinic pulmonologist and principal investigator of the clinical trial currently investigating implications of the animal studies for human patients. “It is truly exciting to see how rapidly these cellular studies were first shown effective in mice, and we now are testing the agent in patients with lung fibrosis,” says Dr. Limper. “This offers a potential rational approach to the treatment of this devastating disorder.”

<b>From Yeast to Mice to Humans</b>

The Mayo researchers studied the biochemical chain of events and communication between cells that transform healthy tissues into uncontrolled fiber-producing growth that eventually blocks lung function and leads to death.

The hallmark of idiopathic fibrosis is the attraction to the lung of abnormal cell types known as fibroblasts. When fibroblasts are acted on by the growth factor TGF-Beta, they transform into spindle-shaped cells known as myofibroblasts. Scientists believe these cells do the real damage to tissue that leads to lung failure. Because TGF-Beta stimulates c-Abl, the researchers decided to test a known c-Abl inhibitor — Gleevec — for its ability to slow or stop the transformation of fibroblasts into myofibroblasts. They found that Gleevec inhibited the transformation.

The researchers got the idea to investigate c-Abl from early studies into the molecular workings of yeast, the most basic life form with nucleated cells. Yeast belong to the same biological group as humans, the eukaryotes. Though the study of yeast and other simpler life forms is fundamental to biomedical research and referred to as “model organism study,” Dr. Leof notes that some skeptics doubt the value of this work. The current investigation is testament to the value of yeast studies, he says. “There is a direct linear relationship between fundamental issues Mark Wilkes was addressing in yeast and in the clinical trials now under way. Without those studies, the trial wouldn't have happened.”

<b>Collaborators and Support</b>

In addition to Drs. Daniels, Leof and Limper, the Mayo Clinic research team included: co-first author Mark C. Wilkes, Maryanne Edens, Ted J. Kottom, and Stephen J. Murphy, Ph.D. The work was supported by Public Health Service Grants from the National Institute of General Medical Sciences and funds from the Robert N. Brewer Family Foundation.


Story Source:

The above story is based on materials provided by Mayo Clinic. Note: Materials may be edited for content and length.


Cite This Page:

Mayo Clinic. "Mayo Clinic Researchers Successfully Use Anticancer Drug To Fight Fatal Lung Disease, Idiopathic Pulmonary Fibrosis." ScienceDaily. ScienceDaily, 16 November 2004. <www.sciencedaily.com/releases/2004/11/041108020203.htm>.
Mayo Clinic. (2004, November 16). Mayo Clinic Researchers Successfully Use Anticancer Drug To Fight Fatal Lung Disease, Idiopathic Pulmonary Fibrosis. ScienceDaily. Retrieved October 1, 2014 from www.sciencedaily.com/releases/2004/11/041108020203.htm
Mayo Clinic. "Mayo Clinic Researchers Successfully Use Anticancer Drug To Fight Fatal Lung Disease, Idiopathic Pulmonary Fibrosis." ScienceDaily. www.sciencedaily.com/releases/2004/11/041108020203.htm (accessed October 1, 2014).

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