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: 8628801
• 负责人: NORMAN E SHARPLESS
• 金额: $ 38.82万
• 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/8628801
• 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; 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; non-invasive imaging; 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（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未得到充分理解。癌症研究这一关键领域的主要障碍之一是缺乏导致区域和远处转移的忠实遗传从头癌症模型。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的复杂微环境中的复杂相互作用。此外，使用免疫功能低下的小鼠进行异种移植的必要性排除了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的阐明。Sharpless和Wong实验室最近生成了由激活的致癌Kras和同时的肿瘤抑制因子Lkb 1丢失驱动的从头小鼠肺癌和黑色素瘤模型，其具有>60%的区域和远处转移率。我们证明了Lkb 1功能的丧失在促进癌症侵袭和转移中至关重要，并剖析了对这一过程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Lkb 1/Kras突变小鼠中进一步改进了这种遗传模型。具有Kras驱动的肺癌或黑素瘤的复合突变小鼠具有同时的Lkb 1和p53损失，具有远端血行转移（100%转移率），因此证明了Lkb 1和p53的不同和独立的肿瘤抑制功能。携带转移的远端器官包括淋巴结、脾、肾、肝、骨和脑，概括了与人肺癌和黑色素瘤相关的观察到的全部转移部位。通过该提议，我们希望进一步表征和改进这些转移性癌症模型，并将体内非侵入性成像标记物（荧光素酶和增强的绿色荧光蛋白）掺入这些复合突变小鼠中，以允许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性扩散的靶向疗法。我们还将与联合国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Lkb 1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，以帮助促进更好的治疗策略。