In vivo murine models of metastasis for therapeutic testing

用于治疗测试的体内转移小鼠模型

基本信息

批准号：
9038322
负责人：
NORMAN E SHARPLESS
金额：
$ 40.02万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-16 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9038322
关键词：
Alleles Area Behavior Biology Brain Cancer Model Cancer cell line Chemicals Collaborations Complex Data Disseminated Malignant Neoplasm Distant Distant Metastasis Event Family Genetic Genetic Engineering Genetic Models Hematogenous Human Imaging Techniques Immune Immune system KRAS2 gene Kidney Laboratories Libraries Liver Location Luciferases Lung MEKs Malignant Neoplasms Malignant neoplasm of lung Modeling Molecular Monitor Mus Mutant Strains Mice Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenic Organ Penetrance Phosphotransferases Primary Neoplasm Process Research Resistance STK11 gene Signal Pathway Site Spleen Stromal Cells TP53 gene Testing Therapeutic Transplantation Tumor Suppressor Genes Tumor Suppressor Proteins Xenograft Model Xenograft procedure anticancer research base bone cancer cell drug discovery enhanced green fluorescent protein high throughput screening imaging biomarker improved in vitro activity in vivo inhibitor/antagonist insight killings lymph nodes melanoma metastatic process mouse model mutant non-invasive imaging novel small molecule targeted treatment tool treatment strategy tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Metastasis is the most lethal feature of human cancers, but the molecular processes that govern metastatic spread are not well understood. One of the major obstacles in this crucial area of cancer research is the lack of faithful genetic de novo cancer model that results in regional and distant metastases. Xenograft models based on cancer cell lines cannot fully recapitulate the intricate interplay in the complex microenvironment of stromal and cancer cells. In addition, the necessity of using immuno-compromised mice for xenograft transplants precludes elucidation of the likely critical interaction between the primary cancer and the immune system in cancer progression. The Sharpless and Wong laboratories have recently generated de novo mouse lung cancer and melanoma models driven by activated oncogenic Kras and concurrent tumor suppressor Lkb1 loss that has a >60% penetrance of regional and distant metastases. We demonstrated that loss of Lkb1 function is crucial in the promotion of cancer invasion and metastasis and dissected the signaling pathways that are crucial to this process. We have now further improved this genetic model by incorporating a p53 mutant allele into the Lkb1/Kras mutant mice. Compound mutant mice with Kras driven lung cancer or melanoma that have concurrent Lkb1 and p53 loss have distant hematogenous metastases (100% penetrance), thus demonstrating distinct and separate tumor suppressor functions for Lkb1 and p53. Distant organs harboring metastases include lymph nodes, spleen, kidney, liver, bone and brain, recapitulating the full spectrum of metastatic sites observed in association with human lung cancers and melanoma. With this proposal, we wish to further characterize and refine these metastatic cancer models and incorporate in vivo non-invasive imaging markers (luciferase and enhanced green fluorescent protein) into these compound mutant mice to permit tracking of the location of micro- metastasis non-invasively using the latest in vivo non-invasive imaging techniques. These models will then be used to test targeted therapeutics that can kill these cancers and inhibit metastatic spread. With collaborators in the UNC Center for Integrative Chemical Biology and Drug Discovery, we will also develop small molecule tool compounds that will enhance metastatic behavior by inhibiting Lkb1 activity. These studies will yield important insights into primary and acquired resistance of these cancers to the various treatments to help facilitate better treatment strategies.

描述（由申请人提供）：转移是人类癌症的最致命特征，但是控制转移扩散的分子过程尚不清楚。癌症研究至关重要领域的主要障碍之一是缺乏忠实的遗传从头癌症模型，导致区域和远处转移。基于癌细胞系的异种移植模型无法完全概括基质和癌细胞复杂的微环境中复杂的相互作用。此外，使用免疫受损小鼠进行异种移植的必要性排除了癌症进展中原发性癌症与免疫系统之间可能关键相互作用的阐明。 Sharpless和Wong实验室最近产生了新的小鼠肺癌和黑色素瘤模型，该模型由激活的致癌性KRAS和同时抑制肿瘤抑制剂LKB1损失，区域和远处转移的渗透率高达60％。我们证明了LKB1功能的丧失对于促进癌症侵袭和转移至关重要，并阐述了对这一过程至关重要的信号传导途径。现在，我们通过将p53突变等位基因掺入LKB1/KRAS突变小鼠中进一步改善了这种遗传模型。具有KRAS驱动的肺癌或黑色素瘤的复合突变小鼠，具有同时性LKB1和p53损失具有遥远的血源转移（100％渗透率），因此表现出对LKB1和p53的独特和独立的肿瘤抑制功能。带有转移的远处器官包括淋巴结，脾脏，肾脏，肝，骨骼和脑，概括了与人类肺癌和黑色素瘤相关的全部转移部位。有了这项建议，我们希望进一步将这些转移性癌症模型进行表征和完善，并将其纳入这些复合突变小鼠中的体内非侵入性成像标志物（荧光素酶和增强的绿色荧光蛋白）中，以允许使用最新的无体性非侵入性非侵入性化的微型转移的位置来跟踪微转移的位置。然后，这些模型将用于测试可以杀死这些癌症并抑制转移扩散的靶向治疗剂。与UNC综合化学生物学和药物发现中心的合作者，我们还将开发小分子工具化合物，这些化合物将通过抑制LKB1活性来增强转移性行为。这些研究将对这些癌症对各种治疗的主要和获得的抗性产生重要的见解，以帮助促进更好的治疗策略。