Modeling breast cancer relapse prevention in mice

描述（由申请人提供）：大多数乳腺癌死亡是由复发引起的，其中潜伏性疾病的部位从休眠状态逃脱。值得注意的是，潜在的病灶残留的疾病，引起乳腺癌复发仍然没有特点，尽管他们的巨大的临床意义。因此，人们对乳腺癌休眠和逃逸的生物学知之甚少。由于乳腺癌患者的潜伏性疾病部位在可预见的未来可能仍然无法进入研究人员，在转基因小鼠中建模休眠乳腺癌提供了一种替代方法：1）揭示肿瘤休眠的生物学基础，2）设计和测试旨在根除休眠疾病的合理治疗策略。 考虑到这些目标，开发了一种小鼠乳腺肿瘤发生模型，其中可以逆转导致乳腺癌发生的遗传事件（Wnt信号通路的激活）。关闭Wnt信号转导会触发这些癌症的消退，但长期存在的疾病病变会持续存在，并且通常在它们从休眠中“逃脱”并引起肿瘤复发之前保持亚临床状态很长一段时间。通过概括休眠乳腺癌的关键临床特征，该模型提供了新的实验途径，以潜伏性疾病的网站，使维持休眠的细胞和分子机制的阐明。此外，该模型中的无病间隔为针对休眠癌症的治疗策略的临床前测试提供了一个窗口。 在该提案的目标1中，将在临床前建模中使用常规细胞毒性药物，以确定如何最佳地安排治疗时间以防止肿瘤逃逸。在此，将比较细胞毒性剂在休眠开始之前、期间和之后给药的结果。在目标2中，基因编码的报告基因将用于跟踪潜伏肿瘤内的肿瘤细胞分裂，以确定休眠的乳腺癌是否由静止的耐药肿瘤细胞亚群维持。这些研究将测试这样一个概念，即根除休眠癌症关键取决于靶向对复发至关重要的静止肿瘤细胞亚群。在目标3中，将使用依赖于乳腺癌中转座子（“跳跃基因”）的动员的遗传筛选来发现驱动肿瘤休眠逃逸的遗传途径。该筛选旨在确定预防复发的新治疗靶点。最终，我们的研究将有助于开发更合理的方法，通过根除休眠疾病的部位来预防乳腺癌复发。 公共卫生相关性：大多数乳腺癌死亡是由于疾病复发，其中潜伏疾病的部位从休眠状态中逃脱。值得注意的是，我们对肿瘤休眠和逃逸的生物学几乎一无所知。通过在转基因小鼠中建立休眠乳腺癌模型，我们提出：1）揭示肿瘤休眠的生物学基础，2）设计和测试旨在根除休眠疾病的合理治疗策略。

DESCRIPTION (provided by applicant): Most breast cancer deaths result from relapse wherein sites of latent disease escape from a dormant state. Remarkably, the latent foci of residual disease that beget breast cancer relapse remain uncharacterized despite their enormous clinical importance. Therefore, very little is known about the biology of breast cancer dormancy and escape. Since sites of latent disease in breast cancer patients are likely to remain inaccessible to researchers for the foreseeable future, modeling dormant breast cancer in genetically-modified mice offers an alternative means to: 1) uncover the biological basis for tumor dormancy, and 2) design and test rational treatment strategies aimed at eradicating dormant disease. With these goals in mind, a mouse mammary tumorigenesis model was developed in which a genetic event responsible for initiating breast cancer (activation of the Wnt signaling pathway) can be reversed. Shutting off Wnt signaling triggers regression of these cancers, but long-lived disease lesions persist and typically remain subclinical for extended periods before they "escape" from dormancy and beget tumor relapse. By recapitulating key clinical features of dormant breast cancer, this model provides novel experimental access to sites of latent disease, enabling elucidation of the cellular and molecular mechanisms that maintain dormancy. Moreover, the disease-free interval in this model provides a window for pre-clinical testing of treatment strategies directed against dormant cancer. In Aim1 of the proposal, conventional cytotoxic agents will be employed in pre-clinical modeling to determine how to optimally time treatment to prevent tumor escape. Here, outcomes will be compared when cytotoxic agents are administered before vs. during vs. after the initiation of dormancy. In Aim 2, genetically encoded reporters will be used to track tumor cell divisions within latent tumors to determine whether dormant mammary cancers are maintained by a subpopulation of quiescent, treatment-resistant tumor cells. These studies will test the concept that eradicating dormant cancer critically depends on targeting a quiescent subset of tumor cells that are crucial for relapse. In Aim 3, genetic pathways that drive escape from tumor dormancy will be discovered using a genetic screen that relies on the mobilization of a transposon ("jumping gene") in mammary cancers. This screen is designed to identify novel therapeutic targets for relapse prevention. Ultimately, our studies will aid in developing more rational approaches for preventing breast cancer relapse by eradicating sites of dormant disease. PUBLIC HEALTH RELEVANCE: Most breast cancer deaths result from disease relapse in which sites of latent disease escape from a dormant state. Remarkably, almost nothing is known about the biology of tumor dormancy and escape. By modeling dormant breast cancer in genetically-modified mice, we propose to: 1) uncover the biological basis for tumor dormancy, and 2) design and test rational treatment strategies aimed at eradicating dormant disease.