Mouse Models and Translational Studies of Endometrial Cancer

子宫内膜癌的小鼠模型和转化研究

基本信息

批准号：
8606327
负责人：
DIEGO H CASTRILLON
金额：
$ 3.25万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606327
关键词：
Automobile Driving Behavior Benign Biological Biological Assay Biological Markers Biological Models Cancer cell line Cell Proliferation Cells Complement DNA Development Disease Endometrial Endometrial Carcinoma Endometrial Neoplasms Epithelial Cells Epithelium Event Female Foundations Gene Targeting Genes Genetic Genetic Models Genetically Engineered Mouse Goals Growth Histologic Human Hyperplasia In Vitro KRAS2 gene Laboratories Lead Lesion Ligation Malignant - descriptor Malignant Female Reproductive System Neoplasm Malignant Neoplasms Mediating Metabolic Modeling Molecular Mus Mutation Neoplasm Metastasis Oncogenes Oncogenic PTEN gene Pathway interactions Penetrance Point Mutation Pre-Clinical Model Proteins Reagent Regimen Research Role STK11 gene Scanning Signal Transduction Sirolimus Specimen Staging TP53 gene Testing Tissues Transgenes Treatment Efficacy Tumor Suppressor Genes Tumor Suppressor Proteins United States Uterine Cancer Uterus base cancer type cell growth cell motility cohort genetic analysis human FRAP1 protein improved in vivo insight mTOR Inhibitor mortality mouse model novel novel therapeutics outcome forecast preclinical study prevent public health relevance reproductive tool translational study tumor tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Endometrial cancer (cancer of the lining of the uterus) is the most common cancer of the female reproductive tract, with about forty thousand new cases in the United States each year. A number of common genetic alterations driving the initial steps of endometrial cancer progression have been documented, such as inactivating mutations of the tumor suppressor gene PTEN. However, PTEN mutations and most other well- documented genetic lesions in endometrial cancers represent early steps driving the formation of benign hyperplasias that remain confined to the uterus. In contrast, little is known about the molecular steps promoting the progression of hyperplasias to truly invasive, lethal cancers that can spread throughout the body. Here we propose to build upon a foundation of prior research carried out in our laboratory. Specifically, we have demonstrated that inactivation of the LKB1 tumor suppressor drives the formation of highly invasive cancers in both mice and humans. The functions of LKB1 are not entirely understood, but it is known to act via its direct target AMPK to inhibit mTOR, a master regulator of cell growth. LKB1 inactivation thus leads to increased mTOR activity, which in turn promotes increased cell proliferation and cancer. Our goals are to 1) gain a more detailed view of the biological impact of LKB1 loss upon endometrial cells and invasive growth; 2) further define the molecular mechanisms by which LKB1 is inactivated in endometrial cancer; 3) study the cooperation of LKB1 with other endometrial cancer genes through the use of an in vivo genetic model system, and thereby also develop more refined genetic models of endometrial cancer; and 4) explore the use of these genetic model systems to validate an mTOR inhibitor as a pathway-specific therapy against endometrial cancer. These interrelated goals will take advantage of unique reagents and approaches including a validated endometrial Cre deletor line that enable gene targeting specifically within endometrial epithelial cells. These studies will also take advantage of a previously developed bank of human endometrial tumor specimens. These studies will lead to insights into the biological and genetic basis of endometrial cancer, create significant opportunities to develop predictive DNA-based or immunohistochemical tests for prognosis, and may someday lead to the development of improved, targeted therapies to treat or prevent endometrial cancer formation and spread.

描述（由申请人提供）：子宫内膜癌（子宫内膜的癌症）是女性生殖道的最常见癌症，每年在美国大约有4万例新病例。已经记录了许多推动子宫内膜癌进展初步步骤的常见遗传改变，例如抑制肿瘤抑制基因PTEN的突变。然而，子宫内膜癌中的PTEN突变和大多数其他有记载的遗传病变代表了驱动良性增生的早期步骤，该步骤仍然局限于子宫。相比之下，关于促进增生到可以散布在整个体内的真正侵入性致命癌的进展的分子步骤知之甚少。在这里，我们建议建立在我们实验室进行的先前研究的基础上。具体而言，我们已经证明了LKB1肿瘤抑制剂的失活驱动小鼠和人类高度侵入性癌症的形成。 LKB1的功能尚不完全了解，但已知它可以通过其直接目标AMPK来抑制细胞生长的主要调节剂MTOR。因此，LKB1失活导致MTOR活性增加，进而促进细胞增殖和癌症的增加。我们的目标是1）对LKB1损失对子宫内膜细胞和侵入性生长的生物学影响更详细的看法； 2）进一步定义了子宫内膜癌中LKB1灭活的分子机制； 3）研究LKB1与其他子宫内膜癌基因的合作，通过使用体内遗传模型系统，从而开发出更多精致的子宫内膜癌遗传模型； 4）探索使用这些遗传模型系统来验证MTOR抑制剂作为针对子宫内膜癌的途径特异性治疗。这些相互关联的目标将利用独特的试剂和方法，包括经过验证的子宫内膜CRE缺失线，该线路能够在子宫内膜上皮细胞内专门靶向基因。这些研究还将利用先前开发的人类子宫内膜肿瘤标本。这些研究将导致对子宫内膜癌的生物学和遗传基础的见解，为预后开发基于预测的DNA或免疫组织化学测试，为预后提供了重要的机会，并且有一天可能会导致改进的，有针对性的疗法以治疗或预防子宫内膜癌的形成和扩散。