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。 在女性中，主要是由于治疗后数年甚至数十年出现的遥远的、不可治愈的复发 原发肿瘤。复发、转移性肿瘤来源于残留的局部和播散性肿瘤细胞池 (DTC)在最初的处理中存活下来，并以假定的休眠状态持续存在于宿主体内。事实上， 治疗后出现骨髓DCs独立地与显著增加的 复发的风险。然而，目前使残留肿瘤细胞保持休眠的机制 人们对此知之甚少，DTC指导的治疗方法也不存在。 因此，DTCs利用的以治疗为目标的生存机制的能力将构成一种 预防乳腺癌复发和相关死亡率的变革性新方法。 癌症患者的治疗越来越多地涉及到有针对性的治疗。特别是，有针对性地抑制 乳腺癌患者中的HER2在辅助环境中代表了一个明显的例子，在这个例子中，残留的肿瘤细胞 可以在海湾里呆很长时间。使用基因工程小鼠模型，忠实地 总结肿瘤的休眠和复发，我们提出了一个假设，即c-met的激活 途径可能是化疗后人和小鼠乳腺癌细胞存活所必需的 或靶向抗HER2治疗。重要的是，虽然c-met在初选中似乎只起到有限的作用 乳腺癌的发生，我们的临床前研究表明，c-met通路的激活可能会 在使休眠的残留肿瘤细胞存活和肿瘤复发方面发挥关键作用。 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 经过治疗的患者将耗尽这一重要的细胞储存库，减少肿瘤复发，从而 提高存活率。具体地说，我们假设c-met的激活有助于生存和复发。 这些机制在患者身上得到了重述。这项建议的具体目的是： (1)确定c-met通路抑制对小鼠残留疾病和复发的影响；以及(2) 通过对患者的杠杆作用，确定c-met抑制对患者残留疾病和复发的影响 根据R01的初始研究阶段的发现启动的一项新的临床试验的样本 申请。这些目标将通过一种新的流式细胞术方法来实现，以分离和评估c-DNA。 在小鼠模型和乳腺癌患者的DTCs中，通过功能评估c-Met的影响 靶向治疗或化疗对DTC存活和复发的通路抑制作用 小鼠模型，以及对原发和转移患者样本的评估。拟议研究的结果 有可能通过以下方式改变乳腺癌幸存者的治疗选择： 休眠DTC的独特脆弱性，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.