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。这些患者常规使用18F-氟代脱氧葡萄糖(FDG)的正电子发射断层扫描(PET)，以确定他们的病情程度，帮助制定放射治疗计划，并在治疗后进行随访。在完成治疗后的三个月内，通过FDG-PET代谢成像确定的肿瘤反应对患者的生存结果具有很高的预测性。大约75%的患者会有完全的代谢反应，25%的患者不会。这项研究的目的是描述完全和不完全反应肿瘤的基于PET的代谢参数。已有研究表明，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，与血管程度、缺氧、增殖率、能量代谢产物和基因表达的差异有关的肿瘤微环境的异质性。但是，人类原发肿瘤整个体积内的代谢异质性还没有被量化或分析其与治疗和结果测量的相关性。PET成像肿瘤代谢功能，并提供了一个独特的机会来评估肿瘤间和瘤内代谢的异质性。该项目的总体目标是验证这样一种假设，即新的基于PET的指标可以评估肿瘤内代谢的异质性，并确定肿瘤内对标准化疗放射治疗无效的区域。这将通过三个具体目标实现：(1)进一步开发和验证基于正电子发射计算机断层扫描的指标来评估肿瘤FDG异质性(葡萄糖代谢)，(2)将这一指标的使用扩展到含3‘-脱氧-3’-18F-胸腺嘧啶核苷(Flt)(细胞增殖的标志物)的PET和带有copper(II)-diacetyl-bis(N4-methylthiosemicarbazone)的PET(铜-ATSM)(缺氧的评估标志物)，以确定与FDG-PET代谢一致(或缺乏)的区域，以及(3)使用这些指标来评估治疗期间的疗效和确定肿瘤内的耐药区域。该项目完成后，将提供一个经过临床验证的基于PET的指标来确定肿瘤的异质性，以预测肿瘤对治疗的反应性。不同的代谢反应区将被确定，以促进我们对这些肿瘤内不同生物间隔的理解，并开发治疗策略来克服这些区域的治疗耐药。公共卫生相关性：晚期宫颈癌患者接受放化疗。在完成治疗后的三个月内，通过FDG-PET代谢成像确定的肿瘤反应对患者的生存结果具有很高的预测性。大约75%的患者会有完全的代谢反应，25%的患者不会。这项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，以便开发治疗策略来克服这些领域的治疗耐药。

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.