Lung Cancer Prognosis: FLT PET and DNA Hypermethylation

肺癌预后：FLT PET 和 DNA 高甲基化

• 批准号: 6956139
• 负责人: HUBERT J VESSELLE
• 金额: $ 54.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6956139
• 关键词: DNA methylation; bioimaging /biomedical imaging; biomarker; cell proliferation; clinical research; human subject; lung imaging /visualization /scanning; neoplasm /cancer classification /staging; nonsmall cell lung cancer; positron emission tomography; prognosis; radiotracer

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the United States. Thirty percent of patients with NSCLC are classified as stage I or II at time of presentation and undergo primary surgical resection with curative intent. However, as a result of initially undiagnosed microscopic metastases, over 50% will develop recurrent disease within two years of surgery. Recent studies have demonstrated that post-resection chemotherapy increases survival of stage I/II patients. But chemotherapy is associated with considerable morbidity and cost. Thus, an accurate method is needed for identifying patients at high risk of recurrence who would benefit most from such additional therapy, while sparing the patients at low risk of recurrence. Currently there is no way of preoperatively and non-invasively identifying the subset of stage I/II NSCLC patients who will recur post resection. Current preoperative staging of NSCLC by 2-[F-18]fluoro-2-deoxy- D-glucose (FDG) Positron Emission Tomography (PET) imaging and Computed Tomography does not permit identification of microscopic metastases. Further, although several studies have suggested that FDG uptake in the primary tumor could predict survival, these studies did not adjust uptake values for size of primary tumor, which is a well-established predictor of survival. When such adjustments are made, FDG uptake is no longer prognostic. Thus new approaches for non-invasive and preoperative prognostic assessment of NSCLC patients are needed. In the proposed study we hypothesize that the uptake of the new radiotracer, 3'-deoxy-3'- [F18]fluorothymidine (FLT), at PET, used in combination with detection of a panel of hypermethylated genes can provide a sensitive and specific approach to identification of stage I/II NSCLC patients at high risk of recurrence after surgical resection. Support for our hypothesis concerning the prognostic utility of FLT used in combination with tissue and/or blood-based biomarkers comes from 1) our pilot studies demonstrating that primary tumor FLT uptake strongly correlates with cellular proliferation, a known predictor of prognosis; 2) studies demonstrating the relationship between detection of 20 hypermethylated genes (in tissue or plasma) and the presence and behavior of cancers including NSCLC. This prognostic information will permit individualization and optimization of therapy for the 41,000 early stage NSCLC patients undergoing surgical resection each year in the United States.

描述（由申请人提供）：非小细胞肺癌（NSCLC）是美国癌症死亡的主要原因。30%的NSCLC患者在就诊时被分类为I期或II期，并接受了根治性手术切除。然而，由于最初未确诊的显微镜下转移，超过50%的患者在手术后两年内会复发。最近的研究表明，切除术后化疗增加了I/II期患者的生存率。但化疗与相当大的发病率和成本有关。因此，需要一种准确的方法来识别高复发风险的患者，这些患者将从这种额外的治疗中获益最多，同时保留低复发风险的患者。 目前还没有办法在术前和非侵入性地确定切除后复发的I/II期NSCLC患者的子集。目前通过2-[F-18]氟-2-脱氧-D-葡萄糖（FDG）正电子发射断层扫描（PET）成像和计算机断层扫描进行的NSCLC术前分期无法识别显微镜下转移。此外，尽管一些研究表明原发性肿瘤中的FDG摄取可以预测生存率，但这些研究没有根据原发性肿瘤的大小调整摄取值，而原发性肿瘤的大小是一个公认的生存率预测因素。当这样的调整，FDG摄取不再是预后。因此，需要新的方法来对NSCLC患者进行非侵入性和术前预后评估。 在拟议的研究中，我们假设在PET中摄取新的放射性示踪剂3 '-脱氧-3'-[F18]氟胸苷（FLT），结合检测一组高甲基化基因，可以提供一种敏感和特异性的方法来识别手术切除后复发风险高的I/II期NSCLC患者。支持我们关于FLT与基于组织和/或血液的生物标志物组合使用的预后效用的假设来自1）我们的初步研究，其证明原发性肿瘤FLT摄取与细胞增殖强烈相关，细胞增殖是已知的预后预测因子; 2）研究表明20个高甲基化基因的检测之间的关系（在组织或血浆中）和癌症（包括NSCLC）的存在和行为。这些预后信息将允许美国每年41，000例接受手术切除的早期NSCLC患者的个体化和优化治疗。