Integration of Biomarker Signatures from Peripheral Blood for Diagnosis, Prognosis, Remission and Recurrence of Lung Cancer

 描述（由申请人提供）：国家肺筛查试验表明，肺癌死亡率降低20%与有严重吸烟史的老年人的常规LDCT筛查相关，但在基于检测到的肺结节进行肺癌筛查阳性的患者中，约96%被证明为假阳性。这些统计数据强调了最大限度地发挥LDCT诊断潜力所需的两个未满足的医疗需求：1）开发诊断平台，以区分常规LDCT识别的恶性和良性结节，以及2）开发廉价的非侵入性方法，可以识别将受益于LDCT随访的风险个体。项目1中拟议的研究利用了基因表达测定的技术进步和肿瘤与免疫系统高度相互作用的丰富证据。我们以前的研究表明，它是可能的，以90%的敏感性和80%的特异性诊断早期肺癌使用PBMC的基因表达特征。拟议的研究将PBMC诊断转化为更具临床可行性的样本收集平台，其额外目标是提高准确性并评估受肺肿瘤存在或去除影响的免疫过程。我们目前的初步研究，支持的假设，这是可以做到的。我们通过评估mRNA和miRNA表达谱来丰富签名开发过程，以评估调节基因表达的互补机制，还将整合与预后相关的自然杀伤细胞和骨髓细胞标志物。我们还在项目2中引入了一种用于肿瘤相关抗原的测定法，所述肿瘤相关抗原是也与循环肿瘤细胞、癌细胞衍生的外来体或其他潜在重要细胞（如癌症干细胞）相关的癌症睾丸抗原（CTA）。我们提供了强有力的初步证据，证明在PBMC衍生的RNA中检测CTA AKAP 4的mRNA是可能的，并且该检测与经验证的肺肿瘤的存在高度相关。这两个项目的初步结果是强有力的。我们还建议整合和扩展这两项研究的特征，并在一个可以评估mRNA和miRNA表达的可靠平台上评估准确性，该平台已经被FDA批准用于乳腺癌预后特征，即Nanostring的nCounter。

 DESCRIPTION (provided by applicant): The National lung Screening Trial has demonstrated that a 20% reduction in lung cancer mortality is associated with routine LDCT screening of older individuals with a heavy smoking history, but of the patients that had a positive screen for lung cancer based on lung nodules detected, approximately 96% proved to be false positives. These statistics highlight two unmet medical needs required to maximize the diagnostic potential of LDCT: 1) the development of diagnostic platforms that will distinguish malignant from benign nodules identified by routine LDCT, and 2) the development of inexpensive, non-invasive methods that can identify at risk individuals who would benefit from follow up with LDCT. The proposed research in Project 1 capitalizes on technical advances for assaying gene expression and abundant prior evidence that tumors are highly interactive with the immune system. Our previous studies demonstrated that it is possible to diagnose early-stage lung cancer with 90% sensitivity and 80% specificity using gene expression signatures from PBMC. The proposed research translates the PBMC diagnostic to a more clinically viable sample collection platform with the additional goal of increasing accuracy and assessing immunological processes affected by the presence or removal of a lung tumor. We present preliminary studies that support the hypothesis that this can be done. We have enriched the signature development process by assessing both mRNA and miRNA expression profiles to assess complimentary mechanisms for regulating gene expression and will also integrate Natural Killer cell and Myeloid cell markers associated with prognosis. We also introduce in Project 2 an assay for tumor associated antigens, the cancer testis antigens (CTAs) also associated with circulating tumor cells, cancer cell derived exosomes or other potentially important cells such as cancer stem cells. We provide strong preliminary evidence that detection of the mRNA for the CTA AKAP4 in PBMC derived RNA is possible and that detection is very highly correlated with the verified presence of a lung tumor. Strong preliminary results are presented for both projects. We also propose to integrate and expand the signatures from these 2 studies and assess accuracy on a single reliable platform that can assess both mRNA and miRNA expression, and is already FDA approved for a breast cancer prognosis signature, the nCounter from Nanostring.