Modeling breast cancer relapse prevention in mice

描述(申请人提供)：大多数乳腺癌死亡是由复发引起的，即潜伏性疾病部位逃脱休眠状态。值得注意的是，导致乳腺癌复发的残留疾病的潜在病灶仍然没有特征，尽管它们具有巨大的临床重要性。因此，人们对乳腺癌休眠和逃逸的生物学知之甚少。由于在可预见的未来，研究人员可能无法接触到乳腺癌患者的潜伏性疾病部位，因此在转基因小鼠中建立潜伏性乳腺癌的模型提供了另一种方法：1)揭示肿瘤潜伏性疾病的生物学基础，2)设计和测试旨在根除潜伏性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，在该模型中，导致乳腺癌的遗传事件(Wnt信号通路的激活)可以被逆转。关闭Wnt信号会触发这些癌症的消退，但长期的疾病损害仍然存在，通常在它们从休眠状态中逃脱并导致肿瘤复发之前，通常会保持较长时间的亚临床状态。通过总结休眠乳腺癌的关键临床特征，该模型提供了对潜在疾病部位的新的实验途径，使阐明维持休眠的细胞和分子机制成为可能。此外，该模型中的无病间隔为针对潜伏期癌症的治疗策略的临床前测试提供了窗口。在该提案的目的1中，将在临床前建模中使用传统的细胞毒剂，以确定如何最佳治疗时间以防止肿瘤逃逸。在这里，将比较细胞毒剂在休眠开始前、休眠期间和休眠后应用的结果。在目标2中，基因编码的记者将被用来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是由一群静止的、耐药的肿瘤细胞维持的。这些研究将检验这样一个概念，即根除潜伏的癌症关键取决于靶向对复发至关重要的一组静止的肿瘤细胞。在目标3中，将使用依赖于乳腺癌中转座子(“跳跃基因”)动员的基因筛查来发现驱动肿瘤休眠逃脱的遗传路径。这一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，通过根除潜伏性疾病来预防乳腺癌复发。 公共卫生相关性：大多数乳腺癌死亡是由于疾病复发造成的，在这种情况下，潜伏的疾病部位会逃脱休眠状态。值得注意的是，人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潜伏期乳腺癌模型，我们建议：1)揭示肿瘤潜伏期的生物学基础，2)设计和测试旨在根除潜伏期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.