INTRA-TUMORAL METABOLIC HETEROGENEITY OF CERVICAL CANCER

描述（申请人提供）：晚期宫颈癌患者接受放化疗治疗。这些患者通常使用18F-氟脱氧葡萄糖（FDG）预处理正电子发射断层扫描（PET）来确定其疾病程度，帮助制定放射治疗计划和治疗后随访。在完成治疗后3个月内，FDG-PET代谢成像确定的肿瘤反应可以高度预测患者的生存结果。大约75%的患者会有完全的代谢反应，25%则不会。本研究的目的是表征完全和不完全反应肿瘤的基于pet的代谢参数。研究表明，在微观层面上，宫颈癌是异质性的。对肿瘤微环境的评估表明，肿瘤微环境的异质性与血管度、缺氧、增殖率、能量代谢物和基因表达的差异有关。但是，在整个人类原发性肿瘤中，代谢肿瘤内异质性尚未被量化或分析其与治疗和结果测量的关系。PET成像肿瘤代谢功能，提供了一个独特的机会来评估肿瘤间和肿瘤内代谢异质性。该项目的总体目标是验证一种假设，即新的基于pet的指标可以评估肿瘤内代谢异质性，并确定肿瘤内对放化疗标准治疗无效的区域。这将通过三个具体目标来实现：(1)进一步开发和验证基于PET的指标来评估肿瘤FDG异质性（葡萄糖代谢），(2)将该指标的使用扩展到含有3'-脱氧-3'- 18f -氟胸苷（FLT）（细胞增殖标志物）的PET和含有铜(II)-二乙酰-双（n4 -甲基硫代氨基脲）（Cu-ATSM）（缺氧评估标志物）的PET，以确定与FDG-PET代谢一致性（或缺乏一致性）的区域。(3)使用这些指标来评估治疗期间的反应并识别肿瘤内的耐药区域。完成后，该项目将提供临床验证的基于pet的指标，以确定肿瘤异质性，预测肿瘤对治疗的反应性。将确定不同代谢反应的区域，以进一步了解这些肿瘤内的各种生物区室，并制定治疗策略来克服这些治疗耐药区域。公共卫生相关性：晚期宫颈癌患者接受放化疗治疗。在完成治疗后3个月内，FDG-PET代谢成像确定的肿瘤反应可以高度预测患者的生存结果。大约75%的患者会有完全的代谢反应，25%则不会。本研究的目的是表征完全和不完全反应肿瘤的基于pet的代谢参数，以便制定治疗策略来克服这些治疗耐药区域。

DESCRIPTION (provided by applicant): Patients with advanced cervical cancer are treated with chemoradiation. Pretreatment positron emission tomography (PET) with 18F- fluorodeoxyglucose (FDG) is routinely utilized for these patients to determine the extent of their disease, to aid in radiation treatment planning, and in follow-up after treatment. Tumor response determined by metabolic imaging with FDG-PET within three months after completing therapy is highly predictive of patient survival outcome. About 75% of patients will have a complete metabolic response and 25% will not. The purpose of this research is to characterize the PET-based metabolic parameters of complete and incompletely responding tumors. It has been shown that on a microscopic level, cervical cancers are heterogeneous. Evaluation of tumor microenvironments has demonstrated heterogeneity relating to variation in degree of vascularity, hypoxia, proliferation rates, energy metabolites, and gene expression. But, metabolic intra-tumoral heterogeneity across the entire volume of primary tumors in humans has not been quantified or analyzed for its association with treatment and outcome measures. PET images tumor metabolic function and presents a unique opportunity to evaluate inter- and intra-tumoral metabolic heterogeneity. The overall goal of this project is to test the hypothesis that novel PET-based metrics can evaluate intra-tumoral metabolic heterogeneity and define areas within tumors that will fail to respond to standard treatment with chemoradiation. This will be achieved by three specific aims: (1) further develop and validate a PET-based metrics to evaluate tumor FDG heterogeneity (glucose metabolism), (2) extend the use of this metric to PET with 3'-Deoxy-3'-18F-fluorothymidine (FLT) (marker of cellular proliferation) and PET with copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) (marker of assessment of hypoxia) to identify areas of metabolic concordance (or lack thereof) with FDG-PET, and (3) use these metrics to evaluate response during therapy and identify resistant areas within tumors. On completion, this project will provide a clinically validated PET-based metric to determine tumor heterogeneity for prediction of tumor responsiveness to therapy. Areas of differing metabolic responsiveness will be identified to further our understanding of the various biologic compartments within these tumors and to develop therapeutic strategies to overcome these areas of treatmen resistance. PUBLIC HEALTH RELEVANCE: Patients with advanced cervical cancer are treated with chemoradiation. Tumor response determined by metabolic imaging with FDG-PET within three months after completing therapy is highly predictive of patient survival outcome. About 75% of patients will have a complete metabolic response and 25% will not. The purpose of this research is to characterize the PET-based metabolic parameters of complete and incompletely responding tumors in order to develop therapeutic strategies to overcome these areas of treatment resistance.