Pilot Human Studies of FMAU PET in Prostate Cancer

 描述（由申请人提供）：前列腺癌影响六分之一的男性，是癌症死亡的第二大原因。前列腺特异性抗原（PSA）筛查的广泛使用通常会促使系统性经直肠超声（TRUS）引导的前列腺活检，从而进行确诊。然而，该程序错过了约40%的前列腺癌，导致重复活检，患者发病率和医疗保健成本显著。因此，存在对图像引导活检的未满足的关键需求，该图像引导活检最大化临床相关肿瘤的检测概率，以避免当前对致命肿瘤的诊断不足（和治疗不足）以及相反地对惰性肿瘤的过度诊断（和过度治疗）。图像引导的前列腺肿瘤检测和定性将为合理的治疗管理策略铺平道路，包括新兴的器官局限性高级别肿瘤的局部治疗。据报道，多参数磁共振成像（mpMRI）可提供相对较高的特异性，但对前列腺癌检测的灵敏度可变。正电子发射断层扫描（PET）与各种示踪剂的潜在用途主要集中在生化复发和去势抵抗转移阶段的疾病。目前，与疑似前列腺癌患者中原发性肿瘤的准确检测、定位和表征相关的任何PET示踪剂的数据都很缺乏，特别是在初始阴性标准TRUS引导活检之后。我们对细胞增殖和细胞应激生物标志物18 F-2 '-氟-5-甲基-1-β-D-阿拉伯呋喃糖基尿嘧啶（18 F-FMAU）与PET的合成和评价有着长期的兴趣和经验。我们的努力包括完成了R21资助的18F-FMAU在前列腺癌动物模型中的临床前评价，自上次审查以来，获得了足够的资金用于IRB-RDRC批准的一名患者的概念验证临床病例研究，最近向美国食品和药物管理局提交了研究性新药申请。我们现在处于一个战略地位，继续沿着这条线的研究与额外的试点人类为基础的可行性试验。因此，本修订R21提案的目的是在疑似原发性前列腺癌的男性中进行18F-FMAU的系统性研究，以在初次诊断时检测、定位和表征原发性肿瘤。这项建议的两个具体目标是：1）对40名根据前列腺特异性抗原水平升高/上升疑似前列腺癌的男性进行18F-FMAU PET/CT的前瞻性临床成像评价，以检测和定位原发性肿瘤，包括计划接受临床mpMRI和TRUS引导活检程序的既往活检阴性的患者，以及2）检查PET和mpMRI衍生的成像参数与活检组织病理学参数以及血清前列腺特异性抗原水平和动力学之间的关联。潜在的假设是18F-FMAU在原发性前列腺癌中积累，允许图像引导活检，其摄取水平反映肿瘤增殖指数。我们认为，增加18F-FMAU PET/CT联合mpMRI引导的前列腺活检将显著改善目前的现状，并影响疑似前列腺癌男性的诊断评价。

 DESCRIPTION (provided by applicant): Prostate cancer affects 1 in 6 men and is the second leading cause of cancer death. Definitive diagnosis is based on systematic transrectal ultrasound (TRUS)-guided prostate biopsy typically prompted by the widespread use of prostate specific antigen (PSA) screening. However, this procedure misses about 40% of prostate cancers leading to repeat biopsies at significant patient morbidity and healthcare cost. Therefore, there is an unmet critical need for image-guided biopsy that maximizes the probability of detection of clinically relevant tumors in order to circumvent the current underdiagnsois (and undertreatment) of lethal tumors and conversely overdiagnosis (and overtreatment) of indolent tumors. Image-guided prostate tumor detection and characterization will pave the way for rational treatment management strategy including the emerging focal therapy for organ-confined high grade tumors. Multiparametric magnetic resonance imaging (mpMRI) has been reported to offer relatively high specificity but variable sensitivity for prostat cancer detection. The potential use of positron emission tomography (PET) with a variety of tracers has primarily focused on the biochemical recurrence and the castrate-resistant metastatic phases of the disease. There is currently paucity of data for any PET tracer relevant to the accurate detection, localization, and characterization of primary tumor in patients with suspected prostate cancer, particularly after an initial negative standard TRUS guided biopsy. We have had a long record of interest and experience with the synthesis and evaluation of the cellular proliferation and cellular stress biomarker, 18F-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F-FMAU) in conjunction with PET. Our efforts have included completion of an R21-funded preclinical evaluation of 18F-FMAU in animal models of prostate cancer, and since the prior review, attainment of sufficient funds for an IRB-RDRC approved proof-of-concept clinical case study in one patient, and recent submission of an Investigational New Drug application to the US Food and Drug Administration. We are now in a strategic position to continue along this line of research with additional pilot human-based feasibility tria. Therefore, the objective of this revised R21 proposal is to perform a systematic study of 18F-FMAU in men with suspected primary prostate cancer for detection, localization and characterization of primary tumor at the time of initial diagnosis. The two specific aims of this proposal are: 1) to perform a prospective clinical imaging evaluation of 18F-FMAU PET/CT for detection and localization of primary tumor in 40 men with suspected prostate cancer based on elevated/rising prostate specific antigen level including those with prior negative biopsy who are scheduled to undergo clinical mpMRI and TRUS-guided biopsy procedure, and 2) to examine the associations between the PET and mpMRI derived imaging parameters and the biopsy histopathology parameters as well as serum prostate specific antigen level and kinetics. The underlying hypothesis is that 18F-FMAU accumulates in primary prostate cancer allowing for image-directed biopsy with an uptake level that is reflective of tumor proliferation index. We believe that addition of 18F-FMAU PET/CT in conjunction with mpMRI directed prostate biopsy will markedly improve the current status quo and impact the diagnostic evaluation of men with suspected prostate cancer.