How to choose pre-clinical mouse model?

2020-06-16

Page View：

After years of experience accumulation, multi-party verification and long-term practical tests, Medicilon’s Pharmacodynamic Department has established a complete animal model library, which can provide various effective animal models to test the effectiveness of drugs according to customer needs. Laboratory animals include non-human primates, dogs, large mice, rabbits, guinea pigs, minipigs, etc. Tumor modeling techniques include methods such as subcutaneous, in situ or metastatic tumor models, and can use living animal animals The luminescence imaging system conducts in situ tumor and metastasis research, and can flexibly develop and build various customized models according to customer needs. This article refers in part to a long article published in the well-known academic journal “Nature”. The content is edited and edited by Medicilon for readers.

Cancer is one of the culprits that take people’s lives. Many people talk about cancer discoloration. The struggle between humans and cancer has never stopped. More and more researchers are investigating the pathogenesis of cancer and new therapies. Despite this, only a handful of new anti-cancer drugs are approved every year. The main reason is that the vast majority of new drugs with good preclinical effects lack good clinical efficacy. Therefore, the rational application and evaluation of innovative preclinical antitumor drugs It is especially urgent and important to promote the combination and unification of preclinical research and clinical efficacy.
As we all know, animal cancer models play a pivotal role in the study of the etiology and pathogenesis of cancer and the evaluation of treatment. Without special reasons, mice are the first model animal for replicating human disease animal models and studying gene function. The mouse cancer model is currently the most commonly used, advanced and recognized preclinical anti-tumor drug effect evaluation system. The model continues to develop with the innovation of tumor treatment strategies and provides important theoretical and practical guidance for cancer treatment methods. This article describes the pre-clinical selection of the most commonly used mouse cancer models and the challenges they face, and briefly describes the application prospects of emerging cancer models, providing a reference for the rational evaluation of drug efficacy before the clinic.
By selecting a reasonable animal model, the positive curative effect data obtained by the pre-clinical research has a good correlation with the clinical efficacy of the drug. The overall judgment of the validity of animal models mainly needs to consider three aspects. The first is apparent validity, which refers to the apparent similarity between the model and the symptoms of the simulated condition; the second is the theoretical validity, which mainly considers the model’s Whether the construction passes a good theoretical foundation; the third is to predict the effectiveness, requiring the model to provide evidence for the prediction of clinical efficacy. Obviously, being able to predict clinical efficacy is the most important basis for judging whether the model is effective. Among them, prediction validity is the most critical.
The important role of pre-clinical mouse models extends from the beginning of drug development, target screening, and evaluation of anti-tumor functions to the clinical trials of drugs. Classic animal models play an important role in the drug discovery phase, which ensures the pharmaceutical properties and activity of the molecules in biological systems. Once the drug candidates are screened, a more complex preclinical model becomes crucial. Once the efficacy and mechanism are confirmed, and the target is verified before the clinic, a complex model should be studied. The effect of the drug on the primary tumor can be determined by the patient’s xenograft solid tumor. The humanized animal model simulates the human immune system and investigates the immunotherapy effects of drugs.

	Model	model description	advantages	disadvantages
Classic model	Subcutaneous (heterotopic implantation)	The same kind or heterogeneous tumor cells can be inoculated into the axilla of mice by subcutaneous transplantation.	• The model is easy to build and convenient to monitor tumor growth (subcutaneous tumors can be directly measured with calipers) •Experimental design saves time and money.	Tumor microenvironment has poor similarity & poor migration
	Orthotopic implantation (xenograft and syngeneic)	Human tumor cell lines are transplanted into immunodeficient mice or tumor cells of mice are inoculated into immune mice, and the inoculation site is the primary site of the tumor.	• The verification and selection of target compounds are more accurate and the method Good repeatability and reproducibility •In situ homologous model can simulate clinical tumor microenvironment	• In vitro passage of cells will cause tumor tissue heterogeneity • Poor predictability for later clinical development
	Patient-derived xenograft (PDX)	Inoculate freshly acquired clinical patient solid tumors into immunodeficient mice	• Can be used as a more widely used efficacy screening • Can be used as a pre-clinical trial • PDX model has certain value in identifying and verifying biomarkers • The model is closer to clinical histology	• The lack of tumor microenvironment hinders the detection of immunomodulators • Subcutaneous transplantation, ex situ • Low rate of transplantation for some types of tumors
	Circulating tumour cellderived PDX (CDX)	inoculates freshly obtained clinical patient blood tumor cells into immunodeficiency mice.	Similar to PDX, its advantage is that it can be used as a model for cases that are difficult to biopsy or undergo surgery (such as early disease).	Cells are few and difficult Collection, short cycle duration
	Humanised PDX	inoculates freshly obtained clinical patient tumors into humanized mice.	Similar to PDX, it is mainly used for immunotherapy research.	• It is easy to cause the failure of the original hematopoietic system • 6-12 months of immunodeficiency • Graft versus host disease
	Personalised PDX (or avatar)	Establish a tumor PDX model for a specific patient to study potential treatment options	Similar to PDX, sometimes used to select patient treatment options	The same disadvantages as PDX in terms of cost and time constraints
	Organoid xenograft	Three-dimensional cell culture of tumors can simulate tumor formation, and can also be transplanted into mice in situ or subcutaneously to construct tumor models.	• Allow tumors to regenerate in vitro and can be adapted to high-throughput screening • Allows more accurate modeling than simple models	• Potential adaptation to in vitro environment or cell selection • Organs must be transplanted into immunodeficient mice
	Genetically engineered mouse models (GEMM)	Genetically engineered mice can form tumors spontaneously, simulating the process of tumor growth and deterioration	• Certain factors of the disease can only be identified for a long time. Includes the development of multiple cell types and primitive organs • A series of therapeutic effects from tumor volume to quantitative metastasis, the design of pre-clinical studies enables it to be realized	• The development time takes 2-10 months, which requires breeding • The same mouse breed, the complexity of the model in terms of genetic variation is not high • Simultaneous overexpression or inactivation of tumor oncogenes and inhibitors will reduce the heterogeneity of clones • Because the primary tumor is overburdened, causing the animal to die prematurely, it is difficult to make an in-depth study of tumor metastasis. Removal of the primary tumor may circumvent this risk
	Somatic tumour models	build specific models by genetically modifying normal cells, constructing tumor cell lines and transplanting them into animals.	• They have many of the same advantages as GEMMS • Can produce the number of mice needed for the experiment • Can be selected or implanted from a large number of mice to achieve the effect of genetic variation • Reporter genes can be transduced at the same time during genetic modification to achieve tracking of transplanted cells in vivo	• The model may not well simulate the early stages of the disease •Need to transplant mouse or human tumor cells into immunodeficient mice