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于复发，其中潜伏的疾病部位从休眠状态逃逸。值得注意的是，引起乳腺癌复发的残留疾病的潜在病灶尽管具有巨大的临床重要性，但仍未被表征。因此，我们对乳腺癌休眠和逃逸的生物学机制知之甚少。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模型提供了另一种方法：1)揭示肿瘤休眠的生物学基础；2)设计和测试旨在根除潜伏性疾病的合理治疗策略。考虑到这些目标，我们建立了一个小鼠乳腺肿瘤发生模型，其中负责启动乳腺癌的遗传事件（Wnt信号通路的激活）可以逆转。关闭Wnt信号会触发这些癌症的消退，但长期的疾病病变持续存在，通常在它们“逃脱”休眠并引发肿瘤复发之前保持较长时间的亚临床状态。通过总结潜伏性乳腺癌的关键临床特征，该模型为潜伏性疾病的部位提供了新的实验途径，从而阐明了维持休眠的细胞和分子机制。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。在本提案的目的1中，常规细胞毒性药物将用于临床前建模，以确定如何最佳时间治疗以防止肿瘤逃逸。在这里，将比较在休眠开始之前、期间和之后使用细胞毒性药物的结果。在Aim 2中，基因编码的报告基因将用于追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一群静止的、抗治疗的肿瘤细胞维持。这些研究将验证这样一个概念，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Aim 3中，将使用一种依赖于乳腺癌转座子（“跳跃基因”）动员的遗传筛选来发现驱动肿瘤摆脱休眠的遗传途径。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，通过根除潜伏性疾病的部位来预防乳腺癌复发。

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.