[F18]FMAU in Prostate Cancer

描述（由申请人提供）：前列腺癌是美国最常见的癌症，也是影响男性癌症死亡的第二大原因。根治性前列腺切除术后可检测血清前列腺特异性抗原（PSA）水平的男性中，约30%有局部复发，而约40%预计有远处病变。其余30% PSA复发的男性根据标准成像方法无法检测到疾病。在这种具有重大公共卫生关切的临床环境中，需要一种准确的基于成像的方法作为早期发现疾病的工具。如果疾病局限于前列腺窝，可以考虑补救性放射治疗。对于男性转移性前列腺癌，在PSA复发时雄激素剥夺（手术或药物）仍然是治疗的基石。我们实验室的初步研究和其他研究人员的辅助研究结果令人鼓舞，促使我们研究[F- 18]-2'-氟-5-甲基-1- β - d -阿拉伯糖氟脲嘧啶（F-18 FMAU）的正电子发射断层扫描（PET）在前列腺癌成像评估中的潜在诊断价值。FMAU是一种胸腺嘧啶类似物，被胸腺嘧啶激酶磷酸化并结合到DNA中，因此对肿瘤增殖成像有用。F-18 FMAU在骨骼和膀胱中没有或很少积累，这使其成为前列腺癌成像的潜在理想PET放射性示踪剂。在这个临床前转化分子成像项目中，我们建议使用显微pet成像系统地研究转移性、局部异种移植和原位人前列腺癌动物模型中F-18 FMAU摄取的水平和程度。我们还将研究肿瘤摄取水平与潜在的关键分子标记（增殖指数，Ki-67和雄激素受体，AR）之间的相关性。我们的项目将为未来在前列腺癌男性患者中进行F-18 FMAU的诊断成像临床试验奠定坚实的基础，特别是在那些表现为生化失败且根据标准成像研究定义没有可定位疾病的大量男性患者中。公共卫生相关性：前列腺癌是美国最常见的癌症，也是影响男性癌症死亡的第二大原因，是一个日益严重的公共卫生问题。早期发现复发和转移性疾病可以早期进行适当的治疗，从而有助于提高生活质量和总体生存率。我们的动物项目基于正电子发射断层扫描（PET）和肿瘤增殖特异性药物（F-18 FMAU），为未来在PSA复发且根据当前标准影像学研究没有可定位疾病的大量男性中进行影像学临床试验奠定了坚实的基础。

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer and the second leading cause of cancer death affecting men in the United States. Approximately 30% of men with detectable serum prostate-specific antigen (PSA) levels after curative radical prostatectomy have local recurrences while about 40% are expected to have distant disease. The remaining 30% of men with PSA relapse will not have detectable disease based on standard imaging methods. The need for an accurate imaging-based method as a tool for detecting the disease early becomes obvious in this clinical setting of major public health concern. If the disease is localized in the prostate fossa, salvage radiation therapy may be considered. In men with metastatic prostate cancer, androgen deprivation (surgical or medical) at the time of PSA relapse remains to be the cornerstone of treatment. Encouraging results from preliminary studies at our laboratory and ancillary results from other researchers have prompted us to investigate the potential diagnostic utility of positron emission tomography (PET) with [F- 18]-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (F-18 FMAU) in the imaging evaluation of prostate cancer. FMAU, first developed in our laboratory, is a thymidine analog that is phosphorylated by thymidine kinase and incorporated in the DNA and therefore is useful for imaging tumor proliferation. F-18 FMAU has no or very little accumulation in bone and in urinary bladder that renders it as a potentially ideal PET radiotracer for imaging in prostate cancer. We propose in this preclinical translational molecular imaging project to systematically study the level and extent of F-18 FMAU uptake in metastatic, localized xenograft as well as orthotopic animal models of human prostate cancer using microPET imaging. We will also examine the correlations among the tumor uptake level and the underlying key molecular markers (proliferation index, Ki-67 and androgen receptor, AR). Our project will form the solid foundation that is needed for future diagnostic imaging clinical trials of F-18 FMAU in men with prostate cancer, specifically in the large group of men who present with biochemical failure and by definition have no localizable disease based on standard imaging studies. PUBLIC HEALTH RELEVANCE: Prostate cancer is a growing public health problem as the most common cancer and the second leading cause of cancer death affecting men in the United States. Early detection of recurrent and metastatic disease allows early appropriate treatment that can then help in enhancing quality of life and overall survival. Our animal project is based on positron emission tomography (PET) with an agent specific for tumor proliferation (F-18 FMAU) forming the solid foundation that is needed for future imaging clinical trials in the large group of men who present with PSA relapse and no localizable disease based on current standard imaging studies.