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。在出现时，有30％的NSCLC患者被归类为I或II期，并以治疗意图进行初级手术切除。然而，由于最初未诊断的微观转移，超过50％会在手术后两年内发展出复发性疾病。最近的研究表明，切除后化疗增加了I/II期患者的存活率。但是化学疗法与大量发病率和成本有关。因此，需要一种准确的方法来识别患者复发风险高的患者，这些患者将从这种额外的疗法中受益最大，同时将患者的复发风险较低。 当前，尚无术前和非侵入性地识别将重复切除后重复出现的I/II期NSCLC患者的子集。 2- [F-18] Fluoro-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的当前NSCLC术前分期，不允许鉴定微观转移。此外，尽管一些研究表明，原发性肿瘤中的FDG吸收可以预测生存，但这些研究并未调整原发性肿瘤大小的吸收值，这是生存的完善预测指标。进行此类调整后，FDG摄取不再是预后的。因此，需要对NSCLC患者进行非侵入性和术前预后评估的新方法。 在拟议的研究中，我们假设新的放射性示踪剂的摄取3'-脱氧-3'- [F18]氟噻胺（FLT）（FLT）（在PET）与检测到一个高甲基化基因的检测结合使用，可以提供一个敏感和特定的基因鉴定手术切除后高风险的I/II期NSCLC患者的方法。支持我们关于与组织和/或血液基生物标志物结合使用的FLT的预后效用的假设的支持，来自1）我们的试验研究表明，原发性肿瘤FLT摄取与细胞增殖密切相关，这是一种已知的预后预测指标； 2）研究证明了20种高甲基化基因（在组织或血浆中）的检测与包括NSCLC在内的癌症的存在和行为之间的关系。该预后信息将允许在美国每年接受手术切除的41,000例NSCLC患者的疗法个性化和优化。