In vivo murine models of metastasis for therapeutic testing

用于治疗测试的体内转移小鼠模型

• 批准号: 8459980
• 负责人: NORMAN E SHARPLESS
• 金额: $ 37.62万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/8459980
• 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; Image; Imaging Techniques; Immune; Immune system; 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; 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; improved; in vitro activity; in vivo; inhibitor/antagonist; insight; killings; lung melanoma; lymph nodes; melanoma; metastatic process; mouse model; mutant; novel; small molecule; therapeutic target; tool; treatment strategy; tumor; tumor progression

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(申请人提供)：转移是人类癌症最致命的特征，但控制转移扩散的分子过程还不是很清楚。在这一癌症研究的关键领域中，主要障碍之一是缺乏可靠的新生癌症基因模型，这种模型会导致区域和远程转移。基于癌细胞系的异种移植模型不能完全概括基质和癌细胞复杂微环境中错综复杂的相互作用。此外，使用免疫受损的小鼠进行异种移植的必要性排除了对原发癌症和免疫系统在癌症进展过程中可能的关键相互作用的阐明。夏普莱斯和王的实验室最近建立了新生的小鼠肺癌和黑色素瘤模型，这些模型是由激活的致癌Kras和同时存在的肿瘤抑制基因Lkb1缺失驱动的，Lkb1缺失具有60%的区域和远处转移外显率。我们证明了Lkb1功能的丧失在促进肿瘤侵袭和转移中是至关重要的，并剖析了在这一过程中至关重要的信号通路。我们现在通过将P53突变等位基因整合到Lkb1/Kras突变小鼠中，进一步改进了这个遗传模型。具有同时缺失Lkb1和P53的Kras驱动的肺癌或黑色素瘤的复合突变小鼠有远处的血液转移(100%外显率)，因此显示出对Lkb1和P53不同的肿瘤抑制功能。存在转移的远处器官包括淋巴结、脾、肾、肝、骨和脑，概括了与人类肺癌和黑色素瘤有关的转移部位的全部范围。有了这个建议，我们希望进一步表征和提炼这些转移癌模型，并在体内整合非侵入性成像标记(荧光素酶和增强型绿色荧光蛋白)到这些复合突变小鼠中，以便使用最新的体内非侵入性成像技术以非侵入性的方式追踪微转移的位置。然后，这些模型将被用于测试可以杀死这些癌症并抑制转移扩散的靶向疗法。我们还将与北卡罗来纳大学综合化学生物学和药物发现中心的合作者一起开发小分子工具化合物，这种化合物将通过抑制Lkb1活性来增强转移行为。这些研究将对这些癌症对不同治疗方法的原始和获得性耐药性产生重要的见解，以帮助促进更好的治疗策略。