Novel Blood Assay for Lung Cancer Detection

描述（由申请人提供）：每年有近100万肺癌（LC）新病例被诊断出来。在美国，据估计2007年大约有213,000个新病例被发现（美国癌症协会）。在确诊的两年内，这些患者中的大多数（约16万）将死亡。本病的诊断通常在常规胸片和/或CT和MRI之后，并在活检和功能性（氟-18标记的脱氧葡萄糖）PET成像后得到证实。肺癌的治疗包括手术、化疗、放射治疗以及更新的实验方法。然而，肺癌患者的五年生存率约为15%，在过去的几十年里没有改变。因此，开发高度特异、敏感和准确的方法来筛查和早期发现隐匿性疾病是势在必行的。肿瘤起源于正常细胞的遗传和表观遗传改变的积累。这些转化的细胞获得新的“癌症特异性”分子指纹（DNA/RNA/蛋白质/脂质），赋予它们独特的表型。我们假设，在各种基于血液的肿瘤特异性特征分析中获得的假阳性和假阴性率是同一个阿喀琉斯之踵的结果：它们都依赖于从“健康”对照者的血液中获得的人群衍生的平均特征谱，即基线/背景特征是/不是特定于被测试个体的基因组成。在本申请中，我们建议(i)开发一种高度创新的基于白细胞的检测方法，(a)将准确预测动物中原发性和/或转移性LC病变的存在，(b)独立于“健康”对照人群的平均特征；（ii）在通过外部成像方式诊断肿瘤之前，检查检测肿瘤对治疗的反应以及动物体内LC存在的能力。我们预计，基于白细胞的血液检测最终将(i)用于检测隐匿性肺肿瘤，具有高特异性、敏感性和准确性；（ii）能够在不知道患有该疾病或有复发性疾病的个体中早期诊断出肿瘤的存在；（iii）将有意义的干预措施移至肿瘤进展路径的更早位置，从而阻止转移性疾病的发展；（iv）监测肿瘤对常规（如手术、化疗）和实验性治疗的反应；(v)允许肿瘤检测、诊断和治疗紧密耦合（即LC治疗的个性化）。

DESCRIPTION (provided by applicant): Every year, close to one million new cases of lung cancer (LC) are diagnosed. In the USA, it is estimated that approximately 213,000 new cases were identified in 2007 (American Cancer Society). Within two years of diagnosis, most of these patients (~160,000) will die. The diagnosis of this disease is usually subsequent to routine chest X-ray and/or CT and MRI and is confirmed upon biopsy and functional (fluorine-18-labeled deoxyglucose) PET imaging. Treatment of lung cancer can involve a combination of surgery, chemotherapy, and radiation therapy as well as newer experimental methods. However, the five-year survival rate of patients with lung cancer is approximately 15% and has not changed over the past several decades. Thus, it is imperative to develop highly specific, sensitive, and accurate methods for screening and early detection of occult disease. Tumors originate from normal cells upon the accumulation of genetic and epigenetic alterations. These transformed cells acquire new "cancer-specific" molecular fingerprints (DNA/RNA/protein/lipid) that give them unique phenotypes. We postulate that the false-positive and false-negative rates obtained in various blood-based, tumor-specific-signature assays are a consequence of the same Achilles' heel: they all depend on population-derived average signature profiles obtained from the blood of "healthy" controls, i.e. the baseline/background signature(s) is/are NOT specific to the genetic makeup of the individual being tested. In this application, we propose to (i) develop a highly innovative WBC-based assay that (a) will accurately predict the presence of primary and/or metastatic LC lesions in an animal, and (b) is independent of population-derived average signatures of "healthy" controls; and (ii) examine the capacity of the assay to detect the response of tumors to therapy as well as the presence of LC in animals before the tumors are diagnosed by external imaging modalities. We anticipate that the WBC-based blood assay eventually will (i) be useful in the detection of occult lung tumors with high specificity, sensitivity, and accuracy; (ii) enable the early diagnosis of tumor presence in individuals who are not known to have the disease or who have recurrent disease; (iii) move meaningful intervention to a much earlier position on the path of tumor progression, thereby forestalling the development of metastatic disease; (iv) monitor the response of tumors to routine (e.g., surgery, chemotherapy) and experimental treatment(s); and (v) allow tumor detection, diagnosis, and treatment to be closely coupled (i.e., personalization of LC therapy).