Abstract 363: Modelling cancer cachexia using a comprehensive panel of heterogeneous esophageal squamous cell carcinoma xenografts for therapeutic application

Abstract

Background: Esophageal squamous cell carcinoma (ESCC) is one of deadliest esophageal malignancies in Asia. Cancer cachexia is a multifactorial body wasting syndrome and is one of the major causes of death in late-stage patients (1). It is characterized by skeletal muscle loss and atrophy, adipose and body wasting, and metabolic dysregulations and stress (1). ESCC is one of the cancer types with the highest morbidity and mortality rates due to cancer cachexia (2). However, there are few effective and approved treatments targeting cancer cachexia. Currently, cancer cachexia animal models are highly limited with few cancer types available as a pre-clinical drug testing platform, with none related to esophageal carcinoma (3). Results: Here we have developed a panel of ESCC patient-derived organoid xenograft (PDOX) mouse model based on our latest patient-derived organoid cultures originating from Hong Kong patients. Our immunodeficient mouse-based PDOX model resembles different cachexic phenotypes that cell line-derived xenograft lacks, including body (skeletal muscle and adipose tissue) wasting and functional signs (e.g. lack of body movement, reduced muscle strength, and loss of appetite). The slow-proliferating characteristic of the ESCC PDOX allows development of a cachexic condition before humane endpoint. Furthermore, our full panel of PDOX lines allowed us to identify the full spectrum, differential cachexia severity across mice bearing different PDOXs, indicating a heterogenous nature. We have comprehensively characterized the cachexia phenotypes and performed proof-of-concept preclinical drug tests using established anti-cachexic drugs; treated PDOX-bearing mice have improved body condition and function compared to the control, which were further verified by histological examinations of tissue samples. Molecular analysis showed that several classic cachexia related gene expressions were down-regulated in isolated liver (Il1b) and inguinal adipose tissues (adipose triglyceride lipase). Conclusions: Our ESCC PDOX model potentially serves as a great pre-clinical cachexia-targeted drug testing platform, providing more treatment options for ESCC patients for better disease management. Acknowledgement: We acknowledge the Research Grants Council (TRS T12-701/17-R to MLL) and the Food and Health Bureau (HMRF 06171566 to VZY) of Hong Kong Special Administrative Region for funding supports. We acknowledge DSMZ for the KYSE cell lines. We acknowledge the HKUMed-CPOS for providing imaging facilities. References:1. Baracos VE, et al. Cancer-associated cachexia. Nat Rev Dis Primers 2018;4:171052. Tanaka Y, et al. Recent advancements in esophageal cancer treatment in Japan. Ann Gastroenterol Surg 2018;2:253-653. Ballaro R, Costelli P, Penna F. Animal models for cancer cachexia. Curr Opin Support Palliat Care 2016;10:281-7 Citation Format: Bryan Chee-chad Lung, Valen Zhuoyou Yu, Ian Yu-hong Wong, Claudia Lai-yin Wong, Desmond Kwan-kit Chan, Fion Siu-yin Chan, Betty Tsz-ting Law, Ka-on Lam, Dora Lai-wan Kwong, Anthony Wing-ip Lo, Simon Law, Maira Li Lung. Modelling cancer cachexia using a comprehensive panel of heterogeneous esophageal squamous cell carcinoma xenografts for therapeutic application [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 363.