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: 7271170
• 负责人: EDWARD J GUNTHER
• 金额: $ 34.5万
• 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/7271170
• 关键词: Accounting; Address; Adjuvant; Adjuvant Therapy; Aftercare; Antineoplastic Agents; Attention; Behavior; Biological; Biology; Breast Adenocarcinoma; Cancer Patient; Cancer Relapse; Clinical; Condition; Cytotoxic agent; Cytotoxin; Data; Diagnostic Neoplasm Staging; Disease; Epithelial; Future; Genetic; Genetic Determinism; Genetically Engineered Mouse; Goals; Human; Knowledge; Left; Lesion; Life; Light; Link; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mediating; Mediator of activation protein; Minority; Modeling; Mus; Neoplasms; Oncogenic; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Play; Pre-Clinical Model; Principal Investigator; Rate; Recurrence; Relapse; Research Personnel; Residual Neoplasm; Residual Tumors; Risk; Role; Signal Transduction; Site; Staging; System; TP53 gene; Testing; Time; Transgenic Mice; Transgenic Organisms; Treatment Protocols; Treatment outcome; Tumor Suppressor Proteins; Tumor stage; Xenograft procedure; base; cancer therapy; chemotherapy; cytotoxic; design; human cancer mouse model; improved; in vivo; in vivo Model; insight; malignant breast neoplasm; mammary epithelium; mortality; mouse model; novel; prevent; programs; response; tool; tumor; tumorigenesis

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(申请人提供)：许多乳腺癌患者在手术后没有发现可检测到的疾病后，会复发数年。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，并导致疾病复发。许多现代乳腺癌治疗是针对MRD(辅助治疗)的，目的是防止复发。值得注意的是，导致乳腺癌复发的潜在MRD病变从未被识别和表征；因此，辅助治疗一直基于显性乳腺癌的生物学和治疗敏感性。然而，乳腺癌复发前潜伏期延长通常表明MRD的生物学特征和明显的恶性是不同的。这项应用的长期目标是提供对MRD的生物学描述，重点是治疗反应的机制。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。 允许对乳腺癌中MRD的临床行为进行忠实建模的转基因小鼠应该有助于测试辅助治疗策略，并询问与介导治疗反应有关的遗传路径。为了在体内建立MRD模型，建立了转基因小鼠，允许在Wnt途径启动的乳腺肿瘤发生的任何阶段可逆激活乳腺上皮中的致癌Wnt信号。在取消致癌信号后，已建立的乳腺肿瘤退化，留下具有潜在恶性潜能的长期、亚临床MRD病变。重要的是，在这个模型中，MRD病变在疾病潜伏期之后会导致肿瘤复发，这为测试辅助治疗策略提供了一个窗口。 患有明显恶性肿瘤或MRD病变的小鼠将在各种治疗条件下进行分析，以检验这样一种假设，即MRD和显性乳腺癌之间的生物差异赋予了不同的治疗反应机制和对这两种形式的肿瘤的不同治疗敏感性。提议的目标如下。 具体目标1：比较使用细胞毒药物作为针对显性恶性肿瘤的主要治疗或作为针对MRD的辅助治疗的结果。具体目标2：确定与介导细胞毒治疗反应有关的肿瘤抑制基因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，以允许研究位于转移部位的显性恶性肿瘤和MRD病变。这些研究将为MRD病变的生物学行为提供新的见解，从而为了解原发乳腺癌和复发乳腺癌之间的关键但鲜为人知的联系提供新的线索。