小鼠肿瘤模型对研究肿瘤生长的生物学过程和抗肿瘤治疗药物的研发非常重要，目前常见的小鼠肿瘤模型有syngenic model, CDX, PDX模型，但不同的小鼠肿瘤模型在应用上及模拟肿瘤真正发生过程上都有不同程度的局限性。比如传统移植性肿瘤模型(TP)在血管化、生长速率、免疫浸润、炎症、肿瘤代谢、肿瘤源性TGF-β的影响等几个关键肿瘤特征上与人类肿瘤存在着不同。相比之下，自发肿瘤动物模型更为接近人类肿瘤的发生，但它们发展缓慢，生长变化大，目前很少用于系统性研究。

百奥赛图老年鼠自发疾病模型项目希望通过对老年鼠进行系统性的研究，建立一套新的、更接近疾病自然发生过程的模型和应用方法，助力新药研发的进程，提高新药研发临床转化率。

Materials and methods

Modified Micro-CT

Diagnosis and Efficacy Study Strategy

  

Results

Diagnosis      

      FVB strain lung tumor diameter ≥1 mm，

Efficacy

      Mice with spontaneous lung tumor can be enrolled into efficacy study

Antibody and small molecular can be evaluated in the lung spontaneous tumor.

Lung spontaneous tumor  Diagnosis

Our micro-CT can realize the structural imaging of small rodents (mice or rats) in vivo in a short time, as well as the non-destructive three-dimensional testing of isolated animal tissues, biomaterials and other samples. It can be widely used in bone research, biomaterial research and development, tumor and cardiovascular disease mechanism research and evaluation, new drug development and so on.

Deep and diversified reconstruction algorithms and post-processing technologies bring clearer picture quality and richer sense of hierarchy. Excellent spatial resolution better than 7.5 μm@10 %MTF, the reconstructed pixel resolution can reach 2 μm.

The system was customized for mice scanning, whose capsule is able to hold 6 mice at the same time. Meanwhile, it meet the needs of scanning accuracy and software analysis, which is a high-throughput screening system.

Micro-CT diagnosis for spontaneous tumor in aged mice

Pathology diagnosis for spontaneous tumor in aged mice

In vivo efficacy study in spontaneous lung tumor models（Pilot study ）

Study Design：

1、Single arm trials

2、Measure drug response according to RECIST guideline

The percentage change of tumor maximum diameter(A), quantitative analysis of tumor maximum diameter(B),  and body weight (C), N=5. 

The percentage change of tumor maximum diameter(A), quantitative analysis of tumor maximum diameter(B),  and body weight (C), N=4. 

Other strains in Biocytogen that can be used for the aged disease research

Data from：Tumor Frequency Grid (jax.org)：http://tumor.informatics.jax.org/mtbwi/dynamicGrid.do

Conclusion
References
[1] M.V. Guerin, V. Finisguerra, B.J. Van den Eynde, N. Bercovici, A. Trautmann, Preclinical murine tumor models: a structural and functional perspective, eLife 9 (2020).
[2] M. Fane, A.T. Weeraratna, How the ageing microenvironment influences tumour progression, Nature reviews. Cancer 20(2) (2020) 89-106. 
[3] C.H. Kugel, 3rd, S.M. Douglass, M.R. Webster, A. Kaur, Q. et al. Weeraratna, Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations, Clinical cancer research : an official journal of the American Association for Cancer Research 24(21) (2018) 5347-5356.

p53基因是迄今发现的，与人类肿瘤相关性最高的基因。p53是抑癌基因，有“基因组守护者”的美誉，可调节细胞周期，参与DNA损伤修复；当细胞受损又无法修复时，p53能够诱导细胞发生凋亡，防止癌变的发生。有研究表明，人类大约一半的肿瘤发生于p53基因突变有关。当p53敲除或突变时，会导致小鼠自发肿瘤的发生，是研究人类肿瘤疾病较好的模型之一。

B-p53-KO rats

Project background

    Tumor suppressor p53 encoded by Tp53 gene contributes to cell cycle arrest, apoptosis, senescence, DNA repair and metabolism. Homozygous Tp53 null rats display onset of spontaneous tumors at 4~6 months of age. B-p53-KO rats is a useful model for studying tumor formation, screening of in vivo carcinogenicity, and examining the efficacy of therapeutic agents.

Targeting strategy

B-p53 KO mice

Project background

The Trp53 gene encodes tumor protein p53, which involves in diverse cellular stresses to regulate target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. P53 protein is expressed at low level in normal cells and at a high level in a variety of transformed cell lines. Mice with homozygous p53 inactivation are developmentally normal but are susceptible to spontaneous tumors.

Targeting strategy