Therapeutic Targeting of Breast Cancer Tumor Initiating Cells

 描述(由申请人提供)：三重阴性乳腺癌(TNBC)如果被认为是其自身疾病，将成为美国女性癌症死亡的第五或第六大原因。对于这些患者，唯一的治疗选择是多药联合化疗，而TNBC肿瘤的化疗敏感性差异很大。众所周知，TNBC在生物学上是异质性的，存在多种可能的亚型。我们假设，这种明显的异质性大部分实际上代表了细胞的可塑性，并且某些形式的异质性实际上可以从一种形式转变为另一种形式；例如，体外和体内结果显示，在基底样细胞系中，存在克拉丁低样细胞，并可以相互转化为更分化的基底样上皮状态。我们建议使用体内模型来验证这一可塑性假说，方法是利用基因工程小鼠(GEM)和患者来源的异种移植(PDX)模型确定一些基因决定因素，这些基因决定因素会驱动细胞进入基底样态(对化疗更敏感)，并在基底样癌中维持TIC。此外，我们将比较原发肿瘤和转移部位(即肺)对标准护理治疗的反应，并使用独特的基于信号通路的记者评估抽动的变化。

 DESCRIPTION (provided by applicant): Triple Negative Breast Cancers (TNBC), if considered its own disease, would rank as the fifth or sixth leading cause of cancer deaths in women in the USA. The only treatment option for these patients is multi-agent chemotherapy, and TNBC tumors are highly variable in terms of their chemotherapy sensitivity. TNBC is also known to be biologically heterogeneous, with multiple possible subtypes present. We hypothesize that much of this apparent heterogeneity actually represents cellular plasticity, and that some forms of heterogeneity can actual morph from one form into another; for example, in vitro and in vivo results show that within basal-like cell lines, claudin-low-like cells exist and can inter-convert nto the more differentiated basal-like epithelial state. We propose to test this plasticity hypothesis using in vivo models by identifying some of the genetic determinants that drive cells into the basal-like state (which is more chemotherapy sensitive), and that maintain TICs in basal-like cancers using both genetically engineered mouse (GEM) and patient derived xenograft (PDX) models. In addition, we will compare the response to standard of care therapies in the primary tumor versus a metastatic site (i.e. lung), and evaluate changes in TICs using unique signaling pathway-based reporters.