Rapid and affordable magneto-nanosensors for ctDNA-guided lung cancer management

项目总结/摘要 非小细胞肺癌（NSCLC）的靶向治疗大大改善了患者的预后 与传统化疗相比。然而，据估计，高达20%的肺癌患者接受 在EGFR突变分析之前的一线治疗，需要快速和廉价的基于血液的 循环肿瘤（CT）DNA测试用于有效的治疗选择。此外，ctDNA可用于再活检， 监测对治疗的反应或对治疗的获得性抗性。我们已经成功地开发出一种 用于检测肺癌“热点”突变组的多路磁纳米传感器测定[靶向 治疗选择或治疗监测和预后。] 该项目的具体目标是： 1)EGFR磁性纳米传感器检测的准确性和与临床结果的相关性 队列。我们假设我们的磁纳米传感器检测可以检测“热点”EGFR突变外显子19， 缺失、L 858 R和T790 M在大型NSCLC患者队列中具有高灵敏度和特异性。此外，本发明还 该测定可很好地适用于预后和治疗反应监测。随访抽血2周 在开始TKI治疗后，可以高度预测无进展生存期。此外，我们假设， 可以使用对磁纳米传感器测定的频繁测试（每2-3个月 成像，如果患者保持良好的反应，并且磁纳米传感器测定可以检测到 在成像前检查疾病进展。 2)在磁纳米传感器阵列上开发广泛的ctDNA突变面板测定[用于NSCLC治疗 选择、监测和预后。]我们假设我们先前开发的EGFR ctDNA磁致伸缩- 纳米传感器突变测定可进一步扩展至包括与第三代TKI相关的突变 耐药机制和其他基因突变，以更好地帮助NSCLC [治疗选择，监测， 的预测]。为此，我们的目标是开发一个ctDNA突变面板，可以帮助确定治疗方案， 对于NSCLC患者，不仅EGFR突变，还包括KRAS、BRAF V600 E、ALK-EML 4融合和 ROS 1融合。[We目的是在整个治疗过程中监测患者的反应性和预后。] 该项目的预期结果是ctDNA EGFR磁纳米传感器测定的临床验证， 扩展和多路复用现有的EGFR检测试剂盒，以包括KRAS、BRAF V600 E、ALK-EML 4融合物，以及 ROS 1融合，并利用该测定[用于有效的治疗选择、预后和/或反应监测。]

Project Summary / Abstract Targeted therapy for the treatment of non-small cell lung cancer (NSCLC) has greatly improved patient outcomes compared to traditional chemotherapy. However, it is estimated that up to 20% of lung cancer patients receive first-line therapy prior to EGFR mutational analysis, necessitating the need for a rapid and cheap blood-based circulating tumor (ct) DNA test for efficient therapy selection. Additionally, ctDNA can be useful for rebiopsy and monitoring of response to therapy or acquired resistance to therapy. We have successfully developed a highly multiplexable magneto-nanosensor assay for the detection of “hot spot” mutation panel for lung cancer [targeted therapy selection or therapy monitoring and prognosis.] Specific aims of the project are: 1) Validate ctDNA EGFR magneto-nanosensor assay accuracy and correlations to clinical outcome on expanded cohort. We hypothesize that our magneto-nanosensor assay can detect “hot spot” EGFR mutations Exon19 deletion, L858R, and T790M with high sensitivity and specificity in a large cohort of NSCLC patients. Additionally, this assay can be well suited for prognosis and therapy response monitoring. A follow-up blood draw 2 weeks after initiating TKI therapy can be highly predictive of progression free survival. Additionally, we hypothesize that frequent testing (every 2-3 months) on the magneto-nanosensor assay could be used in lieu of radiographic imaging if patient maintains favorable response, and that the magneto-nanosensor assay could detect progression of disease prior to imaging. 2) Develop an extensive ctDNA mutation panel assay on magneto-nanosensor arrays [for NSCLC treatment selection, monitoring, and prognosis.] We hypothesize that our previously developed EGFR ctDNA magneto- nanosensor mutation assay can be further expanded to include mutations relevant to third-generation TKI resistance mechanisms and mutations in other genes to better aid in NSCLC [treatment selection, monitoring, and prognosis.] In this aim, our goal is to develop a ctDNA mutation panel that can help identify treatment options for NSCLC patients, not only EGFR mutations but also including KRAS, BRAF V600E, ALK-EML4 fusions, and ROS1 fusions. [We aim to monitor patients throughout their treatment course for responsiveness and prognosis.] The expected outcomes of this project are clinical validation of a ctDNA EGFR magneto-nanosensor assay, expanding and multiplexing the existing EGFR assay to include KRAS, BRAF V600E, ALK-EML4 fusions, and ROS1 fusions, and utilizing the assay [for efficient therapy selection, prognosis, and/or response monitoring.]