Virtual Library

Start Your Search

Vincenza Ciaramella



Author of

  • +

    P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
    • +

      P2.06-42 - AXL, c-MET and VEGFR2 Tyrosine Kinase Receptors as Therapeutic Targets in Malignant Pleural Mesothelioma. (ID 14243)

      16:45 - 18:00  |  Author(s): Vincenza Ciaramella

      • Abstract

      Background

      Malignant pleural mesothelioma (MPM) is a highly aggressive and rare tumour arising from the pleura, primarily associated with asbestos exposure. Therapeutic options are limited to surgical resection, chemotherapy and thoracic radiation, unfortunately no target therapies are currently recommended for MPM. Previous studies suggested that the activation of multiple receptor tyrosine kinases (RTKs) play a central role in MPM pathogenesis and progression. In this context, AXL, c-MET and VEGFR2 overexpression could represent new possible therapeutic targets in MPM.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A Tissue MicroArray of MPM was built, including 40 epithelioid 7 sarcomatoid and 11 mixed. AXL, c-MET and VEGFR2 expression was assessed by Immunohistochemistry using specific antibodies. Fluorescence in Situ Hybridization analysis were performed in order to define AXL and c-MET genes stauts, using LSI AXL 19q13.2/CEN19q probes and LSI MET 7q31.2/CEN7 probes, respectively. Studies in vitro were performed in a wide panel of human MPM cell lines according to different histological type of original tumor, including epithelioid type (NCI-H290, NCI-H2052, NCI-H2452), sarcomatoid type (NCI-H205, NCI-H2373, NCI-H28), and biphasic type (Y-MESO-8A, Y-MESO-14, MSTO-211H).

      4c3880bb027f159e801041b1021e88e8 Result

      AXL expression was observed in 16.6% of cases, while altered gene status in 14.5% of cases, including cases harboring gene amplification and polisomy of chromosome 19. However, no association was observed between AXL immunhistochemical expression and gene amplification. MET protein expression was observed in 20.8% of cases, while gene amplification was identified only in 2.0% of cases. VEGFR2 overexpression was identified in 31.25% of cases. 10.4% of cases showed co-expression of AXL and MET proteins, related significantly with epithelioid histotype (p < 0.05) and 6.25% of cases AXL, c-MET and VEGFR2 co-expression. Studies in vitro showed that multitargets inhibitor blocked cancer cell proliferation, metastasis and angiogenesis in four human mesothelioma cell lines: NCI-H2452, NCI-H2052, NCI-H28 and MSTO. A dose dependent inhibition of cell viability was examined after 72h treatment of human mesothelioma cell lines with increasing doses of multitargets inhibitor, observing a decrease in cell proliferation with IC50 value between 0.5 and 1 µM. Similar effects were detected for apoptosis assay and anchorage-independent colony forming abilities, in particular migration ability of H2052 and MSTO cell lines decreased to about 60% with 0.5 and 1 µM of multitargets inhibitor.

      8eea62084ca7e541d918e823422bd82e Conclusion

      AXL/c-MET/VEGFR2 co-expression represents a frequent event in MPM, especially in epithelioid phenotype, suggesting a possible cooperation of these RTKs in the pathogenesis of this neoplasia. Multitargets AXL/c-MET/VEGFR2 inhibitors could be a promising therapeutic weapon in mesothelioma.

      6f8b794f3246b0c1e1780bb4d4d5dc53