Therapeutic Targeting of Breast Cancer Tumor Initiating Cells

描述(申请人提供)：尽管最近乳腺癌患者的死亡率有所改善，但仍不清楚为什么许多患者即使在对传统内分泌和/或化疗有初步反应后仍会复发。我们已经利用转基因小鼠模型和临床患者解决了这个问题。利用一种独特的可移植的p53缺失的乳腺肿瘤模型，我们已经鉴定出高度浓缩的肿瘤起始细胞(TIC)亚群。体外和体内实验都表明，与大多数肿瘤细胞相比，这些抽搐存在更有效的DNA损伤修复机制。在平行研究中，从乳腺癌患者分离出的TIC中发现了与上皮-间充质转化(EMT)相关的基因特征。这一特征存在于以“克拉丁低”为特征的人类乳腺癌亚群中，最重要的是，在激素和化疗均失败的患者中显著丰富。抽搐通常代表肿瘤内的一小部分细胞，但小鼠和人类的“低”肿瘤似乎都高度富含抽搐。抽动症可能本质上对放化疗引起的DNA损伤具有更强的抵抗力，这在一定程度上解释了它们对常规治疗的抵抗力；它们也被认为是转移扩散、肿瘤休眠和复发的原因。因此，为了帮助阐明TICS固有的治疗耐药性的机制和信号通路，并开发能够克服这种对常规治疗的耐药性的治疗方法，我们提出了以下特定的目标：目的1.分析不同亚型的小鼠P53缺失肿瘤包括Claudin-low/Spindloid类型的TICS。目的2.确定在P53缺失的跛行蛋白低/梭形肿瘤中EMT通路的扰动是否改变了它们的表型特征。目的3.测定抽搐的治疗敏感性。有效靶向乳腺癌肿瘤启动细胞的一个迫切需要是开发改进的临床前模型来测试这些治疗方法。为了满足这一需求，我们已经确定了发生克拉丁低/梭形肿瘤的小鼠模型，其中大部分肿瘤细胞似乎是抽搐。因此，我们相信我们有一个适当的和经过验证的模型来研究重要的信号通路和治疗。这笔多PI赠款将罗森实验室相当多的干细胞和信号通路专业知识与佩鲁实验室的基因组学、生物信息学和治疗学专业知识结合在一起，因此是两者之间的极好协同。) 公共卫生相关性：尽管最近乳腺癌患者的死亡率有所改善，但仍不清楚为什么许多患者即使在对传统内分泌和/或化疗有初步反应后仍会复发。为了有效地靶向被认为对内在治疗耐药和复发负责的乳腺癌肿瘤启动细胞，我们已经确定了发生克拉丁低/梭形肿瘤的临床前小鼠模型，其中大部分肿瘤细胞似乎是肿瘤启动细胞。这些现在为阐明消除这些细胞所需的关键信号通路和治疗方法提供了新的模型。

DESCRIPTION (provided by applicant): Despite recent improvements in mortality for breast cancer patients, it is still not known why many patients relapse even after an initial response to conventional endocrine and/or chemotherapies. We have approached this question using both genetically engineered mouse models and in patients in the clinic. Using a unique transplantable p53 null mammary tumor model we have identified a highly enriched Tumor-Initiating Cell (TIC) subpopulation. Both in vitro and in vivo experiments indicate that more efficient DNA damage repair mechanisms exist in these TICs as compared to the bulk of the tumor cells. In parallel studies, an epithelial- mesenchymal transition(EMT)-related gene signature was identified in TICs isolated from breast cancer patients. This signature was present in the subset of human breast cancers characterized as "claudin-low", and most importantly was significantly enriched in patients who failed both hormonal and chemotherapy. Often TICs represent a small subpopulation of cells within a tumor, but "claudin-low" tumors of both mice and humans appear to be highly enriched in TICs. TICs may be intrinsically more resistant to DNA damage induced by radiation and chemotherapy treatments, thus in part explaining their resistance to conventional treatments; they have also been suggested to be responsible for metastatic dissemination, tumor dormancy and recurrence. Thus, to help elucidate the mechanisms and signaling pathways that are responsible for the intrinsic therapeutic resistance of TICs, and to develop therapies that can overcome this resistance to conventional treatments, the following Specific Aims are proposed: Aim 1. Analysis of TICs in the different subtypes of the murine p53 null tumors including the claudin- low/spindloid class. Aim 2. To determine if perturbation of EMT pathways in the p53 null claudin-low/spindloid tumors alters their phenotypic properties. Aim 3. To determine the therapeutic sensitivity of TICs. One pressing need to effectively target breast cancer tumor initiating cells is the development of improved preclinical models to test these therapies. To address this need, we have identified mouse models that develop claudin-low/spindloid tumors, where the bulk of the tumors cells appear to be TICs. Thus, we believe that we have an appropriate and validated model for the investigation of important signaling pathways and therapeutics. This multiPI grant combines the considerable stem cell and signaling pathway expertise in the Rosen laboratory with the genomics, bioinformatics and therapeutics expertise in the Perou laboratory and, therefore represents an excellent synergy between the two. ) PUBLIC HEALTH RELEVANCE: Despite recent improvements in mortality for breast cancer patients, it is still not known why many patients relapse even after an initial response to conventional endocrine and/or chemotherapies. To effectively target breast cancer tumor initiating cells thought to be responsible for intrinsic therapeutic resistance and recurrence, we have identified preclinical mouse models that develop claudin-low/spindloid tumors, where the bulk of the tumors cells appear to be tumor initiating cells. These now provide novel models for the elucidation of critical signaling pathways and therapeutics required to eliminate these cells.