Minimal Residual Disease and Mechanisms of Breast Cancer Recurrence

项目摘要 尽管早期发现和辅助治疗，乳腺癌仍然是癌症死亡的主要原因 在女性，主要是由于遥远的，无法治愈的复发出现数年，甚至几十年后，治疗的， 原发性肿瘤复发性、转移性肿瘤是由残留的局部和播散性肿瘤细胞引起的 在初次治疗后存活并以假定的休眠状态在宿主中持续存在的DTC。持续增 治疗后骨髓DTC的存在独立地与 复发的风险。然而，目前，使残余肿瘤细胞保持休眠的机制， 和最终复发的认识很少，DTC指导的治疗方法是不存在的。 因此，治疗性靶向DTC所利用的存活机制的能力将构成一种新的治疗方法。 这是一种预防乳腺癌复发及其相关死亡率的变革性新方法。 越来越多的癌症患者的治疗涉及靶向治疗。特别是，靶向抑制 乳腺癌患者在辅助治疗中的HER 2代表了一个明确的例子，其中残留的肿瘤细胞 可以长时间被困在海湾使用基因工程小鼠模型， 概括肿瘤休眠和复发，我们已经提出了一个假设，即c-MET的激活 通路可能是人类和小鼠乳腺癌细胞在化疗后存活所必需的 或靶向抗HER 2治疗。重要的是，尽管c-MET在原发性肝癌中似乎仅发挥有限的作用， 乳腺肿瘤发生，我们的临床前研究表明，c-MET通路的激活可能 在使休眠的残余肿瘤细胞存活和肿瘤复发中起关键作用。 我们假设，有效地使DTC在乳腺癌中持续存在的生存机制失效， 治疗后的患者将耗尽这一关键的细胞库，减少肿瘤复发， 提高生存率。具体来说，我们假设c-MET激活有助于生存和复发。 这些机制在患者中重现。这项建议的具体目标是： (1)确定c-MET途径抑制对小鼠中残留疾病和复发的影响;和（2） 确定c-MET抑制对患者残留疾病和复发的影响， 基于本R 01初始研究阶段的结果启动的新临床试验的样本 应用程序.这些目标将使用一种新的流式细胞术方法来分离和评估c- 通过功能评估c-MET的影响，MET在小鼠模型和乳腺癌患者中的DTCs中 在靶向治疗或化疗后对DTC存活和复发的通路抑制 小鼠模型以及原发性和转移性患者样品的评价。拟议研究的结果 有可能通过针对乳腺癌幸存者的努力， 这是一个独特的潜在DTC的脆弱性，从而防止转移性乳腺癌复发。

Project Summary Despite early detection and adjuvant therapy, breast cancer remains the leading cause of cancer mortality in women, largely due to distant, incurable recurrences arising years, or even decades, after treatment of the primary tumor. Recurrent, metastatic tumors arise from the pool of residual local and disseminated tumor cells (DTCs) that survive primary treatment and persist in the host in a presumed dormant state. Indeed, the presence of bone marrow DTCs following treatment is independently associated with a substantially increased risk of recurrence. At present, however, the mechanisms enabling residual tumor cells to maintain dormancy and ultimately recur are poorly understood, and DTC-directed treatment approaches are non-existent. Consequently, the ability to therapeutically target survival mechanisms utilized by DTCs would constitute a transformational new approach to preventing breast cancer recurrence and the mortality associated with it. Increasingly, treatment for cancer patients involves targeted therapies. In particular, targeted inhibition of HER2 in breast cancer patients in the adjuvant setting represents a clear example in which residual tumor cells can be kept at bay for extended periods of time. Using genetically engineered mouse models that faithfully recapitulate tumor dormancy and recurrence, we have developed an hypothesis that activation of the c-MET pathway may be essential for the survival of human and mouse breast cancer cells subjected to chemotherapy or targeted anti-HER2 therapy. Importantly, whereas c-MET appears to play only a limited role in primary breast tumorigenesis, our preclinical studies suggest the possibility that activation of the c-MET pathway may play a critical role in enabling dormant residual tumor cell survival and tumor recurrence. We hypothesize that effectively disabling the survival mechanisms by which DTCs persist in breast cancer patients following treatment will deplete this critical reservoir of cells, reduce tumor recurrence, and thereby improve survival. Specifically, we hypothesize that c-MET activation contributes to the survival and recurrence of DTCs, and that these mechanisms are recapitulated in patients. The specific aims of this proposal are to: (1) Determine the impact of c-MET pathway inhibition on residual disease and recurrence in mice; and (2) Determine the impact of c-MET inhibition on residual disease and recurrence in patients, by leveraging patient samples from a novel clinical trial initiated based on findings from the initial study period for this R01 application. These aims will be accomplished using a novel flow cytometry approach to isolate and evaluate c- MET in DTCs in mouse models and in breast cancer patients, by functionally evaluating the impact of c-MET pathway inhibition on the survival and recurrence of DTCs following targeted therapy or chemotherapy in mouse models, and evaluation of primary and metastatic patient samples. Results of the proposed studies have the potential to transform treatment options for breast cancer survivors by enabling efforts to target the unique vulnerabilities of dormant DTCs, thereby preventing metastatic breast cancer recurrence.