O50: DEVELOPMENT OF A PATIENT-DERIVED TUMOUR ORGANOIDS FROM METASTATIC BREAST CANCER FOR ASSESSMENT OF NOVEL CLINICALLY ACTIONABLE TARGETS. (27th April 2021)

• Record Type: Journal Article
• Authors: Jagust, P; Varešlija, D; Cocchiglia, S; O'Haloran, PJ; Dablouk, MO; Brett, FM; Cryan, J; Beausang, A; Hudson, L; Hill, ADK; Young, L
• Is Part Of: British journal of surgery. Volume 108(2021)Supplement 1
• Publication Date: 2021-04-27
• Subjects: Surgery -- Periodicals; 617.005
• DOI: 10.1093/bjs/znab117.050
• Languages: English
• ISSNs: 0007-1323

Abstract

Abstract: Introduction: Metastatic breast cancer (MBC) is the main source of mortality in breast cancer patients largely due to lack of effective treatments. Our previous results suggest that tumour transcriptional heterogeneity drives therapy resistance and cancer relapse. While traditional in vitro human cancer cell line models have been widely used for disease modelling, they do not faithfully recapitulate the pathophysiology of MBC. Method: In this study we developed patient-derived tumour organoid cultures from frozen patient-derived (PDX) models of MBC. Using those models we performed preclinical drug screening of investigational and FDA approved therapeutics previously uncovered by us as potentially clinically actionable in MBC. Result: Our results reveal high heterogeneity in the responses to various targeted therapies among tested MBC organoids, which makes them a valuable tool for studying intra-tumor heterogeneity and drug response. Moreover, drug screening identified a divergent set of the breast to brain metastatic MBC organoids that showed high sensitivity to a new class of tyrosine kinase receptors, RET. Conclusion: Taken together, our novel MBC models and methodology applied here provides an important modelling tool to assess the contribution of intra-tumour heterogeneity and microenvironment to drug response as they recapitulate the cellular, structural and biochemical complexity previously observed in our genomic characterisation of MBCs. Application of this type of translational research will enhance the development of new targeted precision medicine strategies and prelude stratification for clinical trials. Abbreviations MBC- Metastatic Breast Cancer; PDX- Patient-Derived Xenografts; FDA- Food and Drug Administration; RET- Receptor Tyrosine Kinase Take-home message: Patient-derived tumour organoid cultures provide an important modelling tool to assess the contribution of intra-tumour heterogeneity and microenvironment to drug response as they recapitulate the cellular, structural and biochemical complexity previously observed in genomic characterisation of metastatic breast cancer. SURGICAL EDUCATION AND TRAINING