INTRA-TUMORAL METABOLIC HETEROGENEITY OF CERVICAL CANCER

描述（由申请人提供）：晚期宫颈癌患者接受放化疗治疗。治疗前使用18F-氟脱氧葡萄糖（FDG）的正电子发射断层扫描（PET）常规用于这些患者，以确定其疾病的程度，以帮助放射治疗计划和治疗后的随访。在完成治疗后三个月内通过FDG-PET代谢成像确定的肿瘤反应高度预测患者的生存结局。大约75%的患者会有完全的代谢反应，25%的患者不会。本研究的目的是表征完全和不完全响应肿瘤的基于PET的代谢参数。已经表明，在微观层面上，宫颈癌是异质性的。对肿瘤微环境的评估已经证明了与血管分布程度、缺氧、增殖率、能量代谢物和基因表达的变化相关的异质性。但是，在人类原发性肿瘤的整个体积中的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联。PET成像肿瘤代谢功能，并提供了一个独特的机会，以评估间和肿瘤内的代谢异质性。该项目的总体目标是检验以下假设：基于PET的新指标可以评估肿瘤内代谢异质性，并确定肿瘤内对标准化放疗无反应的区域。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，以评估肿瘤FDG异质性（葡萄糖代谢），（2）将该度量的使用扩展到具有3 '-脱氧-3'-18F-氟胸苷（FLT）的PET（细胞增殖的标志物）和PET与铜（II）-二乙酰-双（N4-甲基缩氨基硫脲）（Cu-ATSM）（缺氧评估的标志物）来鉴定与FDG-PET代谢一致（或缺乏代谢一致）的区域，和（3）使用这些度量来评价治疗期间的反应并鉴定肿瘤内的抗性区域。完成后，该项目将提供经临床验证的基于PET的指标，以确定肿瘤异质性，从而预测肿瘤对治疗的反应性。不同的代谢反应的领域将被确定，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，以克服这些领域的治疗阻力。公共卫生相关性：晚期宫颈癌患者接受放化疗治疗。在完成治疗后三个月内通过FDG-PET代谢成像确定的肿瘤反应高度预测患者的生存结局。大约75%的患者会有完全的代谢反应，25%的患者不会。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，以开发治疗策略来克服这些治疗抵抗领域。

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.