Point-of care Microfluidics for Early Detection of Cancer

描述（由申请人提供）：早期检测对于为绝大多数实体恶性肿瘤提供治愈性治疗至关重要。来自我们自己的小组和其他人的最新数据表明，循环肿瘤细胞（CTC）可能会大量脱落到患有侵袭性但局限性癌症的患者的血流中。甚至有报告称，在乳腺癌前病变（DCIS）患者中存在异常细胞的扩散。总之，这些观察结果表明，CTC的存在可能是肿瘤血管浸润的早期预兆，而不是癌症演变中的罕见和晚期事件，在最终建立可行的远处转移之前的相当长的一段时间内。这一概念提供了一个从根本上偏离目前的方法，早期癌症检测，这是基于放射线筛查或可靠的血清蛋白质组学方法的发展。检测循环中真正的CTC的存在将成为早期发现癌症的非常强大的工具，但也需要开发高度敏感和可靠的技术。我们已经开发的当前微流体CTC检测方法具有足够的能力来检测某些早期癌症患者中CTC的存在，但它们需要在灵敏度和通量方面大大增强，以最终应用于群体筛查。在这里，我们提出了技术创新，以允许这种敏感和强大的CTC检测策略，利用增强的微流体分离和捕获（目标1），以及用于定量最小CTC数量的分子工具（目标2）。人类研究将得到优先考虑，并将对我们的技术创新和生物学发现进行严格的检验。这是一个哲学上的决定，因为项目研究人员坚信，要在5年内实现“使用技术驱动的方法解决或深刻改善特定健康状况”的量子项目愿景，该项目必须在项目开始时高度关注“真实的”系统。首先是已知的局限性肺癌或乳腺癌患者，然后是新诊断的可疑放射学病变患者，这些病变已被选择进行活检（目标3）。如果成功的话，这里提出的生物工程和分子方法的结合将导致对肺癌或乳腺癌的环境或遗传易感性患者进行大规模筛查研究的迹象。我们共同建立了一个多学科的研究团队，专注于将CTC检测技术扩展到早期检测侵入性但局部化癌症的挑战，并有可能为癌症预防提供革命性的方法。

DESCRIPTION (provided by applicant): Early detection is critical in providing curative therapies for the vast majority of solid malignancies. Recent data from our own group and others suggest that circulating tumor cells (CTCs) may be shed in significant numbers into the blood stream of patients with invasive but localized cancers. Dissemination of abnormal cells has even been reported in patients with preneoplastic breast lesions (DCIS). Together, these observations suggest that, rather than being rare and late events in the evolution of cancer, the presence of CTCs may be an early herald of tumor vascular invasion, preceding a considerable period of time for the eventual establishment of viable distant metastases. This concept provides a radical departure from current approaches to early cancer detection, which are based on either radiographic screening or the development of reliable serum proteomic approaches. Testing for the presence of bona fide CTCs in the circulation would constitute a very powerful tool for early detection of cancer, but also requires the development of highly sensitive and reliable technology. The current approaches to microfluidic CTC detection that we have developed have sufficient capability to detect the presence of CTCs in some patients with early cancers, but they need to be greatly enhanced in both sensitivity and throughput to become valid for eventual application to population screening. Here, we propose technological innovations to allow such sensitive and robust CTC detection strategies, making use of enhanced microfluidic isolation and capture (Aim 1), as well as molecular tools for quantitation of minimal CTC numbers (Aim 2). Human studies will be given priority and will provide a rigorous test of our technological innovations and biological discoveries. This is a philosophical decision in that the project investigators strongly believe that to achieve the Quantum Project vision of "solving or profoundly improving a specific health condition using technology-driven approaches" in a time period of 5 years, the project must have a sharp focus on "real" systems at the onset of the program We propose a graded clinical application of these developing technologies, first in patients with known localized lung or breast cancer, and then in patients with newly diagnosed suspicious radiographic lesions that have been selected for biopsy (Aim 3). If successful, the combined bioengineering and molecular approaches proposed here would lead to indications for large scale screening studies in patients with environmental or genetic susceptibility to lung or breast cancers. Together, we have established a multidisciplinary team of researchers focused on extending CTC detection technologies to the challenge of early detection of invasive but localized cancers, with the potential for revolutionary approaches to cancer prevention.