Establishment of patient-derived organoids from gastrointestinal cancer for antineoplastic evaluation of natural Brazilian semi-synthetic compound (IngC)

• Grant number: 22/05473-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: November 28, 2022
• End date: November 27, 2023
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Rui Manuel Vieira Reis
• Grantee: Ana Laura Vieira Alves
• Supervisor: Eduardo Vilar-Sanchez
• Host Institution: Hospital do Câncer de Barretos. Barretos , SP, Brazil
• Institution abroad: University of Texas MD Anderson Cancer Center (MD Anderson), United States
• Associated to the scholarship: 19/05142-4 - Characterization of the biological effect of semisynthetic compound derived from Euphorbia tirucalli in vitro and in vivo, from the establishment of patients-derived xenografts with gastrointestinal tract tumors, BP.DR

Abstract

Colorectal cancer (CRC) is the third most common cancer in both males and females and the second and fourth leading cause of cancer-related deaths in both sexes worldwide and in Brazil, respectively. Regarding the treatment of CRC, the current standard of care involves tumor removal through surgery and radiotherapy. Lately, more innovative treatments are proposed, such as targeted therapies and immunotherapy. Despite these major advantages, their efficacy is limited due in part to the tumor heterogeneity between and within individual patients. The better understanding of tumor cell biology in every patient could offer the possibility of attaining truly personalized drug-based therapy increasing its effectiveness. Organoids are self-organizing three-dimensional (3D) structures that are grown in vitro from embryological and adult stem cells or induced pluripotent stem cells and preserve many structural and functional features such as cell composition and tissue architecture of their corresponding in vivo organs. Gastrointestinal (GI) organoids models can be generated from epithelial crypts of the mouse, or human samples, which can mimic the genotype and phenotype of parental tumor and retain patient-specific tumors heterogeneity. Besides, organoids developed from patients can be useful tools to improve individual treatment regimens in the context of personalized medicine and for new drug discoveries. The species Euphorbia tirucalli, popularly known as 'aveloz' is used in popular medicine in Brazil for the treatment of various diseases and has been evaluated for its antitumor property. Recently, in collaboration with a Brazilian pharmaceutical, our group reported a novel ingenol semi-synthetic ester derived from the sap of E. tirucalli named Ingenol C. Previous studies with the IngC conducted by our group showed that it promoted a cytotoxic effect on a large panel of cancer cell lines in which colorectal tumor cell lines showed greater sensitivity. Individual patients have different genetic and environmental influences, that may affect how they respond to certain drugs. Therefore, it is important to test the efficacy and cytotoxicity of these potential compounds in a personalized model system, such as an organoid model, in order for a future custom therapy application. The results that will be obtained with the organoid 3D models may contribute even more to elucidate the antineoplastic mechanism of IngC in the colorectal context. It is expected that, from the broad characterization of the biological effect as well as the use of organoid models which are more reliable to reproduce the original tumor microenvironment and the response to treatment, this study will be able to reveal a new antitumor compound from the Brazilian biodiversity that can contribute to the treatment of these tumors. (AU)