Mouse Models of Metastatic Triple-Negative Breast Cancer for Therapeutic Testing

 描述（由申请人提供）：三阴性乳腺癌（TNBC），如果被认为是其自身的疾病，将列为美国女性癌症死亡的第五或第六大原因。这些患者的唯一治疗选择是多药化疗，TNBC肿瘤在化疗敏感性方面具有高度可变性。TNBC也被认为是高度转移性的，大多数死于这种疾病的患者死于由其转移性疾病负担引起的并发症。然而，大多数转移的临床前研究研究转移的扩散和定殖，并且未能集中于已确定的转移的治疗。因此，我们提出的研究的总体目标是利用TNBC的临床前遗传工程（GEM）和患者来源的异种移植物（PDX）模型来确定标准护理化疗方案用于治疗已确定的转移性疾病的功效。具体而言，这些研究将独特地比较TNBC在其原位部位的治疗反应与在免疫受损模型和具有完整免疫系统的模型中建立的肺转移的反应。使用慢病毒载体的最新技术进步允许将荧光和生物发光标记有效引入原发性肿瘤中，以促进转移的非侵入性成像以及在治疗后重新分离转导细胞以进行详细的基因组分析。所提出的治疗方案是基于其治疗人类原发性TNBC疾病的已知功效来选择的。此外，我们还将检查这些TNBC模型中肿瘤起始细胞的频率和生物学，并确定这些TIC特性是否以及如何根据微环境和治疗而变化。由于转移是>90%的癌症相关死亡率的罪魁祸首，因此迫切需要真正有效的抗转移疗法，因此，我们的临床前研究应该为测试这些疗法提供新的范例。

 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 highly metastatic, with most patients who succumb to this disease dying of complications caused by their metastatic disease burden. Most preclinical studies of metastasis, however, study the dissemination and colonization of metastasis, and have failed to focus on the treatment of established metastases. The overall goal of our proposed studies, therefore, is to utilize preclinical Genetically Engineered (GEM) and Patient Derived Xenografts (PDX) models of TNBC to determine the efficacy of standard-of-care chemotherapy regimens for the treatment of established metastatic disease. Specifically, these studies will uniquely compare the therapeutic response of TNBCs in their orthotopic site versus the response of established lung metastases, both in immunocompromised models and those with an intact immune system. Recent technological advances using lentiviral vectors allow the efficient introduction of fluorescent and bioluminescent markers into primary tumors to facilitate both non-invasive imaging of metastases as well as re-isolation of transduced cells following treatment for detailed genomic analyses. The proposed therapeutic regimens have been chosen based upon their known efficacy for the treatment of primary TNBC disease in humans. In addition we will also examine the frequency and biology of Tumor Initiating Cells within these TNBC models, and determine if and how these TIC properties change according to microenvironment, and according to treatment. Because metastases are culpable for >90% of cancer-associated mortality, truly efficacious anti-metastatic therapies are desperately needed and our preclinical studies, therefore, should provide a new paradigm for testing these therapies.