Preclinical Modeling of Latent Breast Cancer in Mice

小鼠潜伏性乳腺癌的临床前建模

• 批准号: 6910390
• 负责人: EDWARD J GUNTHER
• 金额: $ 36.02万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6910390
• 关键词: antineoplastics; breast neoplasms; cytotoxicity; disease /disorder model; genetically modified animals; laboratory mouse; metastasis; minimal residual disease; neoplasm /cancer genetics; neoplastic process; transcription factor; tumor suppressor genes; tumor suppressor proteins

DESCRIPTION (provided by applicant): Many breast cancer patients suffer relapse years after being rendered free of detectable disease by surgery. This indicates that subclinical malignancy in the form of so-called minimal residual disease (MRD) can persist in these patients and beget disease recurrence. Much of modern breast cancer therapy is directed against MRD (adjuvant treatment) with the goal of preventing relapse. Remarkably, the latent MRD lesions that give rise to breast cancer relapse have never been identified and characterized; therefore, adjuvant treatments have been based on the biology and treatment sensitivity of overt breast cancer. However, the prolonged latency that typically precedes breast cancer relapse indicates that the biology of MRD and that of overt malignancy are distinct. The long-term objective of this application is to provide a biological description of MRD with an emphasis on mechanisms of treatment response. Ultimately, these studies will facilitate more rational approaches to curing breast cancer patients via adjuvant treatment. Genetically modified mice that permit faithful modeling of the clinical behavior of MRD in breast cancer ought to be useful for testing adjuvant treatment strategies and interrogating genetic pathways implicated in mediating treatment response. To model MRD in vivo, transgenic mice that permit reversible activation of an oncogenic Wnt signal in mammary epithelium during any stage of Wnt pathway-initiated mammary tumorigenesis were generated. Following abrogation of oncogenic signaling, established mammary tumors regress leaving long-lived, subclinical MRD lesions with latent malignant potential. Importantly, MRD lesions in this model give rise to tumor relapse after periods of disease latency that provide a window for testing adjuvant treatment strategies. Mice harboring either overt malignancy or MRD lesions will be analyzed under a variety of treatment conditions to test the hypothesis that biological differences between MRD and overt breast cancer impart distinct mechanisms of treatment response and distinct treatment sensitivities to these two forms of neoplasia. The proposed Aims follow. Specific Aim 1: To compare outcomes when employing cytotoxic agents either as primary treatment directed against overt malignancy or as adjuvant treatment directed against MRD. Specific Aim 2: To determine whether inactivation of tumor suppressor loci implicated in mediating cytotoxic treatment responses compromises the cytotoxin-sensitivity of either overt tumors or MRD. Specific Aim 3: To extend our reversible tumorigenesis model to permit study of both overt malignancy and MRD lesions residing at metastatic sites. These studies will provide new insights into the biological behavior of MRD lesions and, thereby, shed new light on the crucial but poorly understood link between primary and relapsed breast cancer.

描述（由申请人提供）：许多乳腺癌患者在通过手术消除可检测的疾病后数年复发。这表明，所谓的微小残留病（MRD）形式的亚临床恶性肿瘤可以在这些患者中持续存在并引起疾病复发。许多现代乳腺癌治疗都是针对MRD（辅助治疗）的，目的是预防复发。值得注意的是，引起乳腺癌复发的潜在MRD病变从未被确定和表征;因此，辅助治疗一直基于明显乳腺癌的生物学和治疗敏感性。然而，通常在乳腺癌复发之前的延长的潜伏期表明MRD和明显恶性肿瘤的生物学是不同的。本申请的长期目标是提供MRD的生物学描述，重点是治疗反应机制。最终，这些研究将促进通过辅助治疗治愈乳腺癌患者的更合理的方法。 允许乳腺癌中MRD临床行为的忠实建模的转基因小鼠应该有助于测试辅助治疗策略和询问涉及介导治疗反应的遗传途径。为了在体内建立MRD模型，产生了转基因小鼠，其允许在Wnt途径引发的乳腺肿瘤发生的任何阶段期间乳腺上皮中致癌Wnt信号的可逆活化。在致癌信号传导消除后，已建立的乳腺肿瘤消退，留下具有潜在恶性潜能的长期亚临床MRD病变。重要的是，该模型中的MRD病变在疾病潜伏期后引起肿瘤复发，这为测试辅助治疗策略提供了一个窗口。 将在各种治疗条件下分析携带明显恶性肿瘤或MRD病变的小鼠，以检验MRD和明显乳腺癌之间的生物学差异赋予这两种形式的瘤形成不同的治疗反应机制和不同的治疗敏感性的假设。提出的目标如下。 具体目标1：比较使用细胞毒性药物作为针对显性恶性肿瘤的主要治疗或作为针对MRD的辅助治疗时的结局。具体目标二：确定参与介导细胞毒性治疗反应的肿瘤抑制基因座的失活是否会损害显性肿瘤或MRD的细胞毒素敏感性。 具体目标3：扩展我们的可逆肿瘤发生模型，以允许研究明显的恶性肿瘤和位于转移部位的MRD病变。这些研究将为MRD病变的生物学行为提供新的见解，从而为原发性和复发性乳腺癌之间关键但知之甚少的联系提供新的见解。