Abstract
BackgroundThe treatment of endometrial cancer (EC), the most common gynecological cancer, is currently hampered by the toxicity of current cytotoxic agents, meaning novel therapeutic approaches are urgently required.MethodsA cohort of 161 patients was evaluated for the expression of the receptor for advanced glycation end products (RAGE) in endometrial tissues. The present study also incorporates a variety of in vitro methodologies within multiple cell lines to evaluate RAGE expression and antibody-drug conjugate efficacy, internalisation and intercellular trafficking. Additionally, we undertook in vivo bio-distribution and toxicity evaluation to determine the suitability of our chosen therapeutic approach, together with efficacy studies in a mouse xenograft model of disease.ResultsWe have identified an association between over-expression of the receptor for advanced glycation end products (RAGE) and EC (H-score = Healthy: 0.46, SD 0.26; Type I EC: 2.67, SD 1.39; Type II EC: 2.20, SD 1.34; ANOVA, p < 0.0001). Furthermore, increased expression was negatively correlated with patient survival (Spearman’s Rank Order Correlation: ρ = − 0.3914, p < 0.05). To exploit this association, we developed novel RAGE-targeting antibody drug conjugates (ADC) and demonstrated the efficacy of this approach. RAGE-targeting ADCs were up to 100-fold more efficacious in EC cells compared to non-malignant cells and up to 200-fold more cytotoxic than drug treatment alone. Additionally, RAGE-targeting ADCs were not toxic in an in vivo pre-clinical mouse model, and significantly reduced tumour growth in a xenograft mouse model of disease.ConclusionsThese data, together with important design considerations implied by the present study, suggest RAGE-ADCs could be translated to novel therapeutics for EC patients.
Highlights
The treatment of endometrial cancer (EC), the most common gynecological cancer, is currently hampered by the toxicity of current cytotoxic agents, meaning novel therapeutic approaches are urgently required
One sentence summary The Receptor for Advanced Glycation End products is differentially expressed in endometrial cancers and druggable via an antibody drug conjugate therapeutic approach
The receptor for advanced glycation end products is over expressed in endometrial cancers and associated with reduced survival Endometrial biopsies from 161 patients (70 control, 54 type I EC and 37 type II EC) were obtained as described in Methods (Patient demographics are shown in Additional file 2: Table S1)
Summary
The treatment of endometrial cancer (EC), the most common gynecological cancer, is currently hampered by the toxicity of current cytotoxic agents, meaning novel therapeutic approaches are urgently required. By 2020, estimates suggest there will be 892,000 new cases of gynecological cancer annually, worldwide, leading to 499,000 deaths [1]. Treatment is complicated by the nonspecific and highly-toxic nature of current anticancer drugs, such as DNA alkylating agents or platinum-based drugs used to treat this diseases, necessitating suboptimal dosing to reduce toxicity in normal cells and risking the emergence of drug-resistance in cancer cells. Endometrial cancer (EC), is the most frequently occurring gynecological cancer in developed countries with over 319,000 cases diagnosed worldwide, and in excess of 76,000 deaths annually [2]. Type II EC (10–20% of EC) occurs mostly in older, multiparous women of normal weight [3]
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