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: 8221401
• 负责人: NORMAN E SHARPLESS
• 金额: $ 41.22万
• 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/8221401
• 关键词: Alleles; Area; Behavior; Biology; Brain; Cancer Model; Cancer cell line; Chemicals; Collaborations; Complex; Data; Disseminated Malignant Neoplasm; Distant; Distant Metastasis; Engineering; Event; Family; Genetic; 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. PUBLIC HEALTH RELEVANCE: Metastasis is the most lethal feature of cancer, but is poorly understood. Using faithful, genetically engineered models of lung cancer and melanoma, we will develop effective anti-metastasis therapies for in vivo use.

描述（由申请人提供）：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尚不清楚。癌症研究这一关键领域的主要障碍之一是缺乏忠实的基因从头癌症模型，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重现基质细胞和癌细胞复杂微环境中错综复杂的相互作用。此外，使用免疫功能低下的小鼠进行异种移植的必要性妨碍了阐明原发性癌症和免疫系统在癌症进展中可能的关键相互作用。 Sharpless 和 Wong 实验室最近建立了新的小鼠肺癌和黑色素瘤模型，该模型由激活的致癌 Kras 和同时发生的肿瘤抑制因子 Lkb1 缺失驱动，区域和远处转移的外显率 > 60%。我们证明 Lkb1 功能的丧失对于促进癌症侵袭和转移至关重要，并剖析了对此过程至关重要的信号通路。现在，我们通过将 p53 突变等位基因整合到 Lkb1/Kras 突变小鼠中，进一步改进了这种遗传模型。患有 Kras 驱动的肺癌或黑色素瘤且同时 Lkb1 和 p53 缺失的复合突变小鼠具有远处血行转移（外显率 100%），从而证明了 Lkb1 和 p53 具有独特且独立的肿瘤抑制功能。存在转移的远处器官包括淋巴结、脾、肾、肝、骨和脑，概括了观察到的与人类肺癌和黑色素瘤相关的所有转移部位。通过这项提议，我们希望进一步表征和完善这些转移性癌症模型，并将体内非侵入性成像标记物（荧光素酶和增强型绿色荧光蛋白）纳入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非侵入性地跟踪微转移的位置。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，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各种治疗的原发性和获得性耐药性产生重要的见解，以帮助制定更好的治疗策略。 公共健康相关性：转移是癌症最致命的特征，但人们对其知之甚少。利用肺癌和黑色素瘤的忠实基因工程模型，我们将开发有效的体内抗转移疗法。