Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer

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.

<p>Downregulation of RAGE Inhibits Cell Proliferation and Induces Apoptosis via Regulation of PI3K/AKT Pathway in Cervical Squamous Cell Carcinoma</p>

“…Previous studies have shown that increased RAGE expression significantly promotes the proliferation of vascular smooth muscle cells. 33 Furthermore, similar to the growth-promoting function of RAGE in colon, 34 endometrial, 22 pancreatic, 35 and nonsmall cell lung 36 cancer cells, our present results showed that RAGE overexpression significantly promoted cell proliferation and suppressed apoptosis of SiHa and CaSki cells, whereas knockdown of RAGE resulted in opposite biological processes in SiHa cells. Subsequently, SiHa cells xenografts with RAGE overexpression and knockdown in female nude mice were used to explore the function of RAGE in cervical squamous cancer in vivo.…”

“…RAGE is a central core of a multi-ligand signaling system that drives innate immune-inflammatory responses. 22 Ligand binding to RAGE induces a sustained activation and overexpression of RAGE, which leads to prolonged inflammatory reactions and plays a causative role in human cancers. 10,23 In this work, we identified that RAGE acted as an oncogenic role in cervical squamous cancer and PI3K/AKT pathway was responsible for RAGE-mediated cervical squamous cancer progression.…”

“…Indeed, several small-molecule RAGE antagonists have become available in basic researches for treating cancers. 22,31,32 Hence, targeting RAGE may also become a promising therapeutic strategy for cervical squamous cancer treatment.…”

Immunomodulatory Factors in Primary Endometrial Cell Cultures Isolated from Cancer and Noncancerous Human Tissue–Focus on RAGE and IDO1

“…The receptor for advanced glycation end-products (RAGE) and indoleamine 2,3dioxygenase 1 (IDO1) have been shown to contribute to regulation of immune status of endometrium are currently considered among new molecules of clinical relevance [17,18].…”

“…Metabolic abnormalities in the case of insulin resistance (IR) and obesity have been shown to enhance negative effects of RAGE-mediated inflammation and oxidative stress [35]. Finally, RAGE is considered as a therapeutic target for the development of novel targeted drugs [17].…”