1027P - Preclinical anti-tumor activity of XL880 in nasopharyngeal carcinoma

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Head and Neck Cancers
Authors .1, Z. Li2
  • 1Medical Oncology, The First Affiliated Hospital of Guangzhou Medical University, 510120 - Guangzhou/CN
  • 2Department Of Medical Oncology, Cancer Center of Sun Yat-Sen University, 510060 - Guangzhou/CN

Abstract

Background

Outcomes for locoregionally advanced nasopharyngeal carcinoma (NPC) patients have certainly improved with chemoradiation but eventually local and distant failure remains a very important clinical problem. An earlier study showed increased c-Met and VEGFR2 expression in NPC sample compared to normal nasopharyngeal tissue. XL880 (Foretinib, GSK1363089) is an oral, ATP-competitive small molecular inhibitor against multiple kinases, in particular c-Met and VEGFR2 that are involved in tumor cell growth, migration, and angiogenesis. The objective of this study was to investigate the therapeutic potential of XL880 in NPC.

Methods

Expressions of total and phosphorylated c-Met, VEGFR2, PDGFR, AXL and Tie-2 were evaluated by western blot in a panel of six NPC cell lines. The effect of XL880 on NPC cell proliferation was evaluated by Tilter-Glo luminescent Cell Viability Assay. We further studied the effect of XL880 on NPC cell cycle and apoptosis. In vivo activities of XL880 as single agent and in combination with Cetuximab were investigated in NPC xenografts.

Results

In vitro study showed that XL880 inhibited phosphorylation of both c-Met and VEGFR2. XL880 repressed the growth of both c-Met amplified tumor cells and endothelial cells stimulated with either HGF or VEGF. For the most XL880-sensitive NPC cell line (HK1-LMP1), which harbored the highest levels of both c-Met and VEGFR2, inhibition of cell growth was associated G0/G1 cell cycle arrest as well as significant downregulation of FAK, Mcl-1 and cyclin D1. XL880 eliminated ∼70% of tumor vasculature in xenograft models, inhibited tumor growth, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 decreased invasiveness of primary tumors and reduced metastasis. XL880 in combination with Cetuximab achieved greater antitumor responses than treatment with either agent alone in NPC xenograft models. Additionally, mRNA levels of EGFR ligands TGF alpha and Epiregulin were significantly downregulated by XL880 in vivo.

Conclusions

This is the first report of preclinical activity of c-Met/VEGFR2 inhibitor XL880 in NPC. LMP1 (latent membrane protein 1)-positive NPC shows a higher sensitivity to XL880. Further clinical investigation of XL880 is warranted in NPC patients.

Disclosure

All authors have declared no conflicts of interest.