Point-of care Microfluidics for Early Detection of Cancer

描述（由申请人提供）：早期发现对于绝大多数实体恶性肿瘤的治疗至关重要。我们自己的研究小组和其他人的最新数据表明，循环肿瘤细胞（ctc）可能会大量脱落到侵袭性但局限性癌症患者的血液中。异常细胞的播散甚至在肿瘤前乳腺病变（DCIS）患者中也有报道。总之，这些观察结果表明，ctc的存在可能是肿瘤血管侵袭的早期前兆，而不是癌症进化中的罕见和晚期事件，在相当长的一段时间内最终建立可行的远端转移。这一概念从根本上改变了目前的早期癌症检测方法，这些方法要么基于放射学筛查，要么基于可靠的血清蛋白质组学方法。检测循环中是否存在真正的CTCs将是早期发现癌症的一个非常有力的工具，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检测方法已经有足够的能力在一些早期癌症患者中检测到CTC的存在，但它们需要在灵敏度和通量上得到极大的提高，才能最终应用于人群筛查。在这里，我们提出了技术创新，利用增强的微流体分离和捕获（目标1），以及用于最小CTC数量定量的分子工具（目标2），以实现这种敏感和稳健的CTC检测策略。人类研究将被优先考虑，并将为我们的技术创新和生物学发现提供严格的测试。这是一个哲学上的决定，因为项目研究人员坚信，要实现量子项目的愿景，即在5年的时间里“利用技术驱动的方法解决或深刻改善特定的健康状况”，项目必须在项目开始时就明确关注“真正的”系统。我们建议对这些开发中的技术进行分级临床应用，首先在已知的局限性肺癌或乳腺癌患者中，然后是新诊断出可疑的影像学病变并选择活检的患者（目的3）。如果成功，这里提出的生物工程和分子结合的方法将导致对肺癌或乳腺癌环境或遗传易感性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，以应对侵袭性局部癌症的早期检测挑战，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. PUBLIC HEALTH RELEVANCE: The next major hurdle in the management and treatment of cancer patients is early detection. The proposed point-of-care microchip to non-invasively isolate circulating tumor cells from the peripheral blood of cancer patients and ultimately general population for early detection has the potential to revolutionize the management of cancer patients with concomitant increase in survival rates.