DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted November 8, 2016
Lynn Heasley, Ph.D., University of Colorado Denver

Lynn Heasley, Ph.D., University of Colorado Denver

Lynn Heasley, Ph.D.
University of Colorado Denver


Mesothelioma is a cancer of the cells that make up the surrounding tissue of internal organs including the lungs. Environmental exposure to fibrous minerals, most commonly asbestos, is the major risk factor for developing mesothelioma. Risk of exposure to asbestos at service locations and during deployment to the developing world, where asbestos is still used as a major building material, puts military members at increased incident rates with military Veterans at ~30% of all mesothelioma cases (1). To date, there are no FDA-approved targeted therapies for malignant mesothelioma, and patients are offered only three options for treatment: Surgery, non-selective chemotherapeutics, or radiation. Patient prognosis remains poor with median survival after initial diagnosis ranging from 6 to 13 months (2). Thus, a more thorough investigation into the malignant transformation processes in mesothelioma is needed to drive the development of new and effective therapies.

With funding from a Fiscal Year 2012 Peer Reviewed Cancer Research Program Discovery Award, Dr. Lynn Heasley examined the role of the fibroblast growth factor receptor family of proteins (FGFR) in mesothelioma development. FGFR proteins are members of the receptor tyrosine kinase (RTK) class of signaling molecules, which regulate vital cellular processes. These types of proteins initiate intracellular signaling cascades through interaction with extracellular stimuli, effectively acting as a cellular surveillance system to monitor and respond to environmental changes. Abnormal FGFR expression and signaling are observed in many tumor types, though a role in mesothelioma has yet to be determined. To establish a link between FGFR signaling and mesothelioma development, Dr. Heasley mapped the expression of various members of the FGFR family and found that both FGFR1 and FRGR2 proteins were abundant in many human mesothelioma cell lines, with FGFR1 detected in 60% of all cell lines tested.

To examine whether the functional expression of FGFR members is an essential element in the maintenance and growth of mesothelioma, Dr. Heasley performed two sets of molecular silencing experiments on a panel of cell lines. An approach that employed inhibition of FGFRs with the tyrosine kinase inhibitor ponatinib was used. Ponatinib is an FDA-approved drug for the treatment of chronic myeloid leukemia that, when applied to mesothelioma cell lines, reduced neoplastic growth characteristics for some members of the cell line panel. From gene expression data, it was determined that this ponatinib effect correlated with FGFR1 expression. To directly test the requirement of FGFR1 activity in mesothelioma, the effect of individual gene expression modification was studied. Upon reduction of FGFR1 gene expression, the clonal expansion of mesothelioma cells with high basal FGFR1 levels was significantly reduced while modified expression of FGFR2 or 3 had no effect on growth characteristics. This direct inhibitory method supports the theory that FGFR1 plays a significant role in driving the growth of these mesothelioma cell lines.

The functional inhibition of FGFR1 supports the idea that RTK signaling is a driver of malignant cell growth in a subset of human-derived mesothelioma cell lines. More research is needed to better address the utility of tyrosine kinase inhibitors in managing malignant mesothelioma, but Dr. Heasley's research has established a foundation from which superior therapeutic strategies may arise based on a better understanding of the key elements of the malignant transformation process of mesothelioma.

Lynn Heasley, Ph.D., University of Colorado Denver
Front row (left to right):Lynn Heasley (PhD), Lindsay Marek (MS, MBA), Natalia Gurule (BS), Trista Hinz (BS, MS) Back row (left to right): Jacob Calhoun (BS), Sean Korpela (BS), Dan Sisler (BS)

Works cited:

(1) https://www.asbestos.com/veterans/
(2) Marek LA, Hinz TK, von Mässenhausen A, Olszewski KA, Kleczko EK, Boehm D, Weiser-Evans MC, Nemenoff RA, Hoffmann H, Warth A, Gozgit JM, Perner S, Heasley LE. 2014. Nonamplified FGFR1 is a growth driver in malignant pleural mesothelioma. Mol Cancer Res 12(10):1460-1469.

Link:

Public and Technical Abstracts: Targeting Fibroblast Growth Factor Receptor Signaling Pathways in Mesothelioma

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Last updated Tuesday, November 8, 2016