02583nas a2200325 4500000000100000008004100001260001500042653002800057653001700085653002200102653003400124653003400158653003500192653002300227100001700250700001900267700002100286700001700307700001900324700002200343700001800365700003400383700001600417245008300433856007200516300001100588490000800599520163600607022001402243 2023 d c2023-07-0110aCancer microenvironment10aCancer niche10aCancer stem cells10aCancer therapeutic challenges10aCancer-associated fibroblasts10ainduced pluripotent stem cells10aPreclinical models1 aSean Hockney1 aJessica Parker1 aJasmin E. Turner1 aXanthea Todd1 aStephen Todryk1 aRoben Ger Gieling1 aGerrit Hilgen1 aDavina Camargo Madeira Simoes1 aDeepali Pal00aNext generation organoid engineering to replace animals in cancer drug testing uhttps://www.sciencedirect.com/science/article/pii/S0006295223001776 a1155860 v2133 aCancer therapies have several clinical challenges associated with them, namely treatment toxicity, treatment resistance and relapse. Due to factors ranging from patient profiles to the tumour microenvironment (TME), there are several hurdles to overcome in developing effective treatments that have low toxicity that can mitigate emergence of resistance and occurrence of relapse. De novo cancer development has the highest drug attrition rates with only 1 in 10,000 preclinical candidates reaching the market. To alleviate this high attrition rate, more mimetic and sustainable preclinical models that can capture the disease biology as in the patient, are required. Organoids and next generation 3D tissue engineering is an emerging area that aims to address this problem. Advancement of three-dimensional (3D) in vitro cultures into complex organoid models incorporating multiple cell types alongside acellular aspects of tissue microenvironments can provide a system for therapeutic testing. Development of microfluidic technologies have furthermore increased the biomimetic nature of these models. Additionally, 3D bio-printing facilitates generation of tractable ex vivo models in a controlled, scalable and reproducible manner. In this review we highlight some of the traditional preclinical models used in cancer drug testing and debate how next generation organoids are being used to replace not only animal models, but also some of the more elementary in vitro approaches, such as cell lines. Examples of applications of the various models will be appraised alongside the future challenges that still need to be overcome. a0006-2952