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• 11543

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  P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11591

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    P2.06-048 - Malignant mesothelioma lacking merlin shows enhanced sensitivity to the FAK Inhibitor VS-6063: Evaluation of merlin/NF2 status in clinical samples (ID 3377)

    09:30 - 09:30  |  Author(s): D.T. Weaver
    • Abstract

    Background
    Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung often resulting from prior exposure to asbestos. Median overall survival following frontline chemotherapy with pemetrexed/cisplatin is approximately 12 months. There is no established second line treatment. New therapeutic modalities are urgently needed to improve the prognosis of MPM patients. Approximately 50% of MPM patients exhibit homozygous disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. VS-6063 is a potent, orally active, inhibitor of focal adhesion kinase (FAK).

    Methods
    Proliferation of drug-treated mesothelioma cell lines in 3-dimensional (3D) Matrigel culture was assessed by MTS, and orthotopic MPM xenograft growth in the lungs was measured in vehicle- vs. VS-6063-treated SCID mice. Since absence of merlin expression can theoretically result from several mechanisms including NF2 mutation and chromosome 22 abnormalities, we assessed NF2 gene deletion by FISH and merlin protein levels by IHC in the same human mesothelioma tumor samples.

    Results
    Among a panel of mesothelioma cell lines in 3D culture, MPM lines lacking expression of merlin protein were found to be especially sensitive to the selective FAK inhibitor VS-6063. In contrast, MPM cell lines with wild-type merlin were less sensitive with EC~50~ values greater than 1 μM. Accordingly, oral dosing of VS-6063 induced significant tumor growth inhibition in a merlin-negative mesothelioma model pre-implanted in the lungs of mice. To enable the planned stratification of MPM patients by merlin status, an immunohistochemistry (IHC) assay has been optimized to quantify merlin protein levels. A merlin IHC H-score below the defined cutoff was associated with loss of at least one copy of chromosome 22, indicating that chromosomal deletion is an important mechanism of merlin loss in mesothelioma patients.

    Conclusion
    These data support the clinical development of VS-6063 for treatment of malignant pleural mesothelioma patients stratified by merlin/NF2 status. VS-6063 is being studied in a registration-directed mesothelioma trial.