Polymerase epsilon-based mouse and derived organoid models of intestinal cancer

项目总结/摘要 肠癌是男性和女性中第三常见的恶性肿瘤和癌症相关死亡的原因。 妇女不幸的是，我们对潜在的肠道生物学和癌症的理解的最新进展- 相关途径尚未转化为显著改善的患者结果。虽然许多动物 已经开发了肠癌模型，主要基于β-连环蛋白途径的失调， 目前已知人类癌症的一些关键特征（特别是肿瘤突变负荷）对肿瘤的发生至关重要， 进展和治疗反应，尚未在动物模型中充分建模或研究， 肠癌 最近，基因组测序的努力导致了一个肠癌突变表型的发现 其中管家DNA聚合酶的校正结构域内的单个氨基酸取代 导致人类癌症中描述的最高突变率（超突变）。 与人类癌症不同，基因工程动物模型表现出非常低的突变率，限制了它们的应用。 用于研究肿瘤内异质性和竞争、免疫应答和免疫检查点 治疗，现在已知是人类肿瘤生物学的重要方面。我们建议克服这些困难， 在肠癌动物模型中的局限性，建立在1）在产生 癌症动物模型和用于其开发的新遗传工具2）良好表征的条件性PoleP 286 R 我们以前用来开发子宫内膜癌的强大模型的等位基因和3）基因组学方面的专业知识， 炎症、肠癌和肠道疾病的小鼠模型。这些模型不仅有用， 为了概括POL驱动的肠癌，也为了人源化任何肠癌小鼠模型， 关于突变负担。本提案是为了响应PAR-20-131而提交的， 开发用于转化癌症研究的哺乳动物模型。

PROJECT SUMMARY/ABSTRACT Intestinal cancer is the 3rd most common malignancy and cause of cancer-related deaths in both men and women. Unfortunately, recent advances in our understanding of the underlying intestinal biology and cancer- related pathways have not translated to significantly improved patient outcomes. While numerous animal models of intestinal cancer have been developed, mostly based on misregulation of the β-catenin pathway, some key features of human cancers (particularly tumor mutational burden) now known to be critical for tumor progression and therapy response, have not been adequately modelled or investigated in animal models of intestinal cancer. More recently, genome sequencing efforts led to the discovery of an intestinal cancer mutator phenotype where single amino acid substitutions within proofreading domains of the housekeeping DNA polymerases result in the highest mutation rates described in human cancers (ultramutation). Unlike human cancers, genetically-engineered animal models exhibit very low mutation rates, limiting their utility for studies of intratumoral heterogeneity and competition, immune responses, and immune checkpoint therapies, now known to be essential aspects of human tumor biology. We propose to overcome these limitations in intestinal cancer animal models by building upon 1) a strong track record in the generation of cancer animal models and novel genetic tools for their development 2) a well-characterized conditional PoleP286R allele that we previously used to develop a robust model of endometrial cancer and 3) expertise in genomics, inflammation, intestinal cancer, and mouse models of intestinal disease. These models will be useful not only to recapitulate POL-driven intestinal cancers, but also to humanize any intestinal cancer mouse model with respect to mutational burden. This proposal is submitted in response to PAR-20-131 to expand and improve the development of mammalian models for translational cancer research.