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

 描述(申请人提供)：国家肺部筛查试验表明，肺癌死亡率降低20%与对有大量吸烟史的老年人进行常规LDCT筛查有关，但在根据检测到的肺结节进行肺癌筛查呈阳性的患者中，约96%被证明是假阳性。这些统计数据突显了最大限度地发挥LDCT诊断潜力所需的两个尚未满足的医疗需求：1)开发诊断平台，区分常规LDCT确定的良恶性结节；2)开发廉价、非侵入性的方法，可以识别哪些高危个人将从LDCT的后续检查中受益。项目1中提出的研究利用了分析基因表达的技术进步和大量先前证明肿瘤与免疫系统高度相互作用的证据。我们以前的研究表明，利用PBMC的基因表达特征诊断早期肺癌具有90%的敏感性和80%的特异性。这项拟议的研究将PBMC诊断转化为一个临床上更可行的样本收集平台，另一个目标是提高准确性，并评估受肺部肿瘤存在或切除影响的免疫过程。我们提出的初步研究支持这一假设，即这是可以做到的。我们通过评估mRNA和miRNA表达谱来丰富标志性开发过程，以评估调节基因表达的互补机制，并将整合与预后相关的自然杀伤细胞和髓样细胞标志物。我们还在项目2中介绍了一种肿瘤相关抗原的检测方法，即肿瘤睾丸抗原(CTA)，这种抗原也与循环中的肿瘤细胞、癌细胞来源的外切体或其他潜在的重要细胞，如癌症干细胞相关。我们提供了强有力的初步证据，证明在PBMC来源的RNA中检测CTA AKAP4的信使核糖核酸是可能的，并且该检测与证实存在肺肿瘤高度相关。两个项目都给出了强有力的初步结果。我们还建议整合和扩展这两项研究的签名，并在单个可靠的平台上评估准确性，该平台可以评估mRNA和miRNA的表达，并且已经被FDA批准用于乳腺癌预后签名，即NanoStringnCounter。

 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.