Survival and Recurrence of Dormant Cancer Cells

描述（申请人提供）：复发性乳腺癌是一种典型的不治之症。因此，治疗后乳腺癌复发的倾向是临床结果的最重要决定因素。对于许多类型的人类癌症，残留的肿瘤细胞——被称为微小残留疾病——在治疗后仍然存在，而传统的临床检测无法检测到。在乳腺癌病例中，20-40%的原发性乳腺癌患者存在播散性肿瘤细胞，没有任何临床或组织病理学转移迹象。这些细胞有能力在假定的休眠状态下在组织中存活长达20年，要么作为孤立细胞，要么作为微转移细胞。最终，残留细胞从这种潜伏状态重新出现并恢复生长，导致癌症复发。因此，微小残留病变、肿瘤休眠和复发构成了肿瘤进展的基本表现，是导致绝大多数乳腺癌死亡的原因。尽管乳腺癌进展的这些方面具有无与伦比的临床重要性，然而，其背后的机制在很大程度上是未知的。由于休眠的残余肿瘤细胞构成了复发性癌症的储存库，缺乏专门针对这些细胞的治疗方法-以及我们对其生物学的缺乏了解-构成了成功治疗人类癌症的主要障碍。因此，靶向治疗的发展旨在阻断残留肿瘤细胞赖以生存和生长的途径，这将是预防癌症复发的一种有吸引力的方法。为了实现这一目标，我们开发并验证了一系列多西环素诱导的MYC、HER2/neu、Wnt1和akt过表达乳腺癌的转基因小鼠模型，这些模型显示了人类乳腺癌进展的关键特征，包括微小残留疾病、肿瘤休眠和复发。在这个应用中，我们将使用这些模型来阐明促进肿瘤休眠和复发的分子途径。本应用的具体目的是确定c-Met和Fbw7/Notch通路在乳腺肿瘤休眠和复发中的作用。我们的初步数据表明，这些途径中的每一种都可能促进休眠残余肿瘤细胞的存活和复发。降低乳腺癌死亡率最终需要大大提高对微小残留疾病、肿瘤休眠和复发的认识。通过探索乳腺癌进展的这些关键表现，本应用中提出的研究将通过靶向肿瘤细胞的生存机制来促进维持肿瘤细胞处于休眠状态或诱导其死亡的治疗目标。这一知识有助于开发更有效的治疗方法，从而极大地改变数百万乳腺癌幸存者的治疗选择。

DESCRIPTION (provided by applicant): Recurrent breast cancer is typically an incurable disease. As a consequence, the propensity of breast cancers to recur following treatment is the most important determinant of clinical outcome. For many types of human cancer, residual tumor cells - referred to as minimal residual disease - remain following treatment that are not detected by conventional clinical testing. In the case of breast cancer, disseminated tumor cells are present in 20-40% of primary breast cancer patients lacking any clinical or histopathological signs of metastasis. These cells have the ability to survive in a presumed dormant state within tissues for up to 20 years, either as solitary cells or as micrometastases. Ultimately, residual cells re-emerge from this latent state and resume growth, leading to cancer recurrence. As such, minimal residual disease, tumor dormancy, and recurrence constitute fundamental manifestations of tumor progression that are responsible for the vast majority of breast cancer deaths. Despite the unrivaled clinical importance of these aspects of breast cancer progression, however, the mechanisms underlying them are largely unknown. Since dormant residual tumor cells constitute the reservoir from which recurrent cancers invariably arise, the lack of therapeutic approaches specifically targeted against these cells - as well as our lack of understanding about their biology-constitutes major obstacles to the successful treatment of human cancers. As such, the development of targeted therapies designed to block pathways on which residual tumor cells depend for survival and growth would represent an attractive approach to preventing cancer recurrence. To pursue this goal, we have developed and validated a series of doxycycline-inducible transgenic mouse models for MYC, HER2/neu, Wnt1, and Akt-overexpressing breast cancers that display key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. In this application, we will use these models to elucidate the molecular pathways that contribute to tumor dormancy and recurrence. The specific aims of this application are to determine the role of the c-Met and Fbw7/Notch pathways, in mammary tumor dormancy and recurrence. Our preliminary data suggest that each of these pathways may promote the survival and recurrence of dormant residual tumor cells. Reducing breast cancer mortality will ultimately require a substantially improved understanding of minimal residual disease, tumor dormancy, and recurrence than currently exists. By probing these critical manifestations of breast cancer progression, the studies proposed in this application will advance the therapeutic goals of maintaining tumor cells in a dormant state or inducing their death by targeting their survival mechanisms. This knowledge could facilitate the development of more effective therapeutic approaches that would dramatically alter the treatment options available to millions of breast cancer survivors. PUBLIC HEALTH RELEVANCE: Residual breast cancer cells that survive therapy have the ability to survive in a dormant state following treatment and linger unrecognized for more than a decade before emerging as recurrent disease. Since recurrent breast cancer is typically an incurable disease, and since recurrent breast cancers typically arise from disseminated tumor cells, understanding the biology of minimal residual disease and elucidating the molecular pathways that contribute to tumor dormancy and recurrence is a critical priority in breast cancer research. This application is focused on that goal.