Point-of care Microfluidics for Early Detection of Cancer

描述(申请人提供)：早期发现对于为绝大多数实体恶性肿瘤提供根治疗法至关重要。来自我们自己的小组和其他人的最新数据表明，循环中的肿瘤细胞(CTC)可能大量进入侵袭性但局限性癌症患者的血流中。乳腺癌前病变(DCIS)患者中甚至有异常细胞扩散的报道。综上所述，这些观察结果表明，在癌症的演变过程中，CTC的存在并非罕见的晚期事件，而可能是肿瘤血管侵犯的早期预兆，为最终建立可行的远处转移提供了相当长的一段时间。这一概念与目前的癌症早期检测方法有很大的不同，目前的方法要么是基于放射筛查，要么是基于可靠的血清蛋白质组方法的发展。检测循环中是否存在真正的四氯化碳将是早期发现癌症的一个非常强大的工具，但也需要开发高度敏感和可靠的技术。目前我们开发的微流控CTC检测方法已经足以检测一些早期癌症患者中CTC的存在，但它们的灵敏度和吞吐量都需要大大提高，才能有效地最终应用于人群筛查。在这里，我们提出了技术创新，以实现这种灵敏和强大的四氯化碳检测战略，利用增强型微流控分离和捕获(目标1)，以及用于量化最低四氯化碳数量的分子工具(目标2)。人类研究将被优先考虑，并将为我们的技术创新和生物发现提供严格的考验。这是一个哲学上的决定，因为项目调查人员坚信，要在5年的时间内实现Quantum Project的愿景，“使用技术驱动的方法解决或深刻改善特定的健康状况”，该项目必须在项目开始时将重点放在“真实”系统上。我们建议对这些正在开发的技术进行分级临床应用，首先是已知的局部性肺癌或乳腺癌患者，然后是新诊断的可疑放射学损伤患者，这些患者已被选择进行活组织检查(目标3)。如果成功，这里提出的生物工程和分子方法的结合将导致对环境或遗传易感性肺癌或乳腺癌患者进行大规模筛查研究的适应症。我们共同建立了一个多学科的研究团队，专注于扩展CTC检测技术，以应对早期检测侵袭性但局限性癌症的挑战，并有可能采用革命性的癌症预防方法。

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.