Poster Presentation 25th Lorne Cancer Conference 2013

Improving patient immune responses to monoclonal antibody therapies in epithelial cancer through changes in cellular trafficking (#211)

Lingbo Hu 1 , Rachael Barry 1 , Daniel Gaffney 1 , David Pryor 2 , Sandro V Porceddu 2 , Duncan Lambie 3 , Matthew Foote 2 , Bryan Burmeister 2 , Jeff Strutton 3 , Nicholas A Saunders 1 , Fiona Simpson 1
  1. University of Queensland Diamantina Institute and Princess Alexandra Hospital, Brisbane, Queensland, Australia
  2. Cancer Services, Radiation Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  3. Pathology Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia

The epidermal growth factor receptor (EGFR) plays a role as a central mediator of multiple cellular functions including cell proliferation, differentiation and survival. Dysregulation of this molecule has been shown to be involved in tumour genesis and progression in a variety of human cancers. Therefore, EGFR has been a target for developing anti-cancer therapies. Several EGFR-targeting monoclonal antibodies (mAb), such as Cetuximab and Panitumumab are approved by the FDA for treatments of metastatic colorectal cancer (mCRC) and Head and Neck squamous cell carcinoma (HNSCC). Despite encouraging clinical outcomes, significant variance in patient responses has been frequently reported.

Our research is focused on EGFR trafficking status and on improving anti-EGFR mAb treatments. We propose that ligand-induced EGFR endocytosis is dysregulated in ~ 40% of human squamous cell carcinoma (SCC) and is associated with the pathobiology and pathogenesis of SCC. We also propose that the receptor trafficking status impacts on the efficacy of the EGFR-targeting mAb treatments, and might be a potential predictor of patient prognosis. Therefore manipulating receptor trafficking may benefit patients with EGFR-over-expressing tumours.

We have further developed assays for tumour cell killing in response to anti-EGFR therapy and found that manipulation of cellular trafficking increases therapy efficacy. We present data showing that the main mechanism of anti-EGFR monoclonal therapies in tumour regression, as opposed to growth inhibition, is antibody dependent cellular cytotoxicity (ADCC) mediated by Natural Killer cell populations. We show data on the use of small molecule inhibitors in improving tumour killing by ADCC. Findings from this work may also impact on the clinical management of other tumours in which target receptors are spatially regulated, including fibroblast growth factor receptor (FGFR) in melanoma, vascular endothelial growth factor receptor (VEGFR) in colorectal carcinoma and insulin-like growth factor (IGFR) in sarcomas.