Abstract
Early oesophageal adenocarcinoma (OA) and pre-neoplastic dysplasia may be treated with endoscopic resection and ablative techniques such as photodynamic therapy (PDT). Though effective, discrete areas of disease may be missed leading to recurrence. PDT further suffers from the side effects of off-target photosensitivity. A tumour specific and light targeted therapeutic agent with optimised pharmacokinetics could be used to destroy residual cancerous cells left behind after resection. A small molecule antibody-photosensitizer conjugate was developed targeting human epidermal growth factor receptor 2 (HER2). This was tested in an in vivo mouse model of human OA using a xenograft flank model with clinically relevant low level HER2 expression and heterogeneity. In vitro we demonstrate selective binding of the conjugate to tumour versus normal tissue. Light dependent cytotoxicity of the phototherapy agent in vitro was observed. In an in vivo OA mouse xenograft model the phototherapy agent had desirable pharmacokinetic properties for tumour uptake and blood clearance time. PDT treatment caused tumour growth arrest in all the tumours despite the tumours having a clinically defined low/negative HER2 expression level. This new phototherapy agent shows therapeutic potential for treatment of both HER2 positive and borderline/negative OA.
Highlights
An estimated 9,000 new cases of oesophageal adenocarcinoma (OA) are diagnosed each year in the UK and the 5-year survival is 15% [1]
22% (18/83) of tumours were defined as human epidermal growth factor receptor 2 (HER2) positive according to EMEA guidelines for gastric cancer [21]
The proportion of HER2 positive tumours was higher in more proximal oesophageal tumours than those originating from the oesophagogastric junction (28.2% vs 15.9%) but not significantly so (Fishers exact p = 0.19 (Figure 1A and 1B)
Summary
An estimated 9,000 new cases of oesophageal adenocarcinoma (OA) are diagnosed each year in the UK and the 5-year survival is 15% [1]. Current treatments for early stage OA and BE that is www.oncotarget.com localised to the mucosal layer include endoscopic resection (EMR) and ablation. These therapies are gastroenterologist directed and despite high quality imaging, small tumours are still hard to detect and can have indistinct edges, this can lead to incomplete removal of the cancer and subsequent recurrence. Over-zealous treatment to reach deeper or suspicious but negative tumour margins can lead to normal tissue damage and oesophageal strictures or perforations [3, 4]
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