Journal Article

A preclinical platform for assessing long-term drug efficacy exploiting mechanically tunable scaffolds colonized by a three-dimensional tumor microenvironment

Carpentier, Nathan, Pauwels, Jarne, De Vlieghere, Elly, Van Dorpe, Jo, Descamps, Benedicte, Van Vlierberghe, Sandra, Blondeel, Eva, Mestach, Johanna, Ceelen, Wim, Denys, Hannelore, Riemann, Sebastian, Claes, Kathleen, Vral, Anne, Minsart, Manon, Ghobeira, Rouba, Van de Vijver, Koen, De Geyter, Nathalie, Debbaut, Charlotte, Baeyens, Ans, De Wever, Olivier, De Geest, Bruno G., Fieuws, Charlotte, Gevaert, Kris

2023

Overview

Background Long-term drug evaluation heavily relies upon rodent models. Drug discovery methods to reduce animal models in oncology may include three-dimensional (3D) cellular systems that take into account tumor microenvironment (TME) cell types and biomechanical properties. Methods In this study we reconstructed a 3D tumor using an elastic polymer (acrylate-endcapped urethane-based poly(ethylene glycol) (AUPPEG)) with clinical relevant stiffness. Single cell suspensions from low-grade serous ovarian cancer (LGSOC) patient-derived early passage cultures of cancer cells and cancer-associated fibroblasts (CAF) embedded in a collagen gel were introduced to the AUPPEG scaffold. After self-organization in to a 3D tumor, this model was evaluated by a long-term (> 40 days) exposure to a drug combination of MEK and HSP90 inhibitors. The drug-response results from this long-term in vitro model are compared with drug responses in an orthotopic LGSOC xenograft mouse model. Results The in vitro 3D scaffold LGSOC model mimics the growth ratio and spatial organization of the LGSOC. The AUPPEG scaffold approach allows to test new targeted treatments and monitor long-term drug responses. The results correlate with those of the orthotopic LGSOC xenograft mouse model. Conclusions The mechanically-tunable scaffolds colonized by a three-dimensional LGSOC allow long-term drug evaluation and can be considered as a valid alternative to reduce, replace and refine animal models in drug discovery. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,American Association for the Advancement of Science (AAAS),한국생체재료학회
• Subject: 3D cancer model / Animal models / Biomaterials / Biomechanics / Cancer / Cancer therapies / Cell suspensions / Chemistry and Materials Science / Chemotherapy / Collagen / Drug discovery / Drug efficacy / Drug evaluation / Drug resistance / Drug therapy, Combination / Ethylene glycol / Fibroblasts / Fourier transforms / Heat shock proteins / Hsp90 protein / Hydrogels / Long-term / Materials Science / Mechanical properties / Micro-environment / Mutation / NMR / Nuclear magnetic resonance / Oncology / Ovarian cancer / Patients / Polyacrylate / Polyethylene glycol / Pre-clinical / Research Article / Spheroids / Stiffness / Telecommunication systems / Tumor microenvironment / Tumors / Xenografts / 의공학