Pilot Human Studies of FMAU PET in Prostate Cancer

 描述(申请人提供)：前列腺癌影响每6名男性中的1名，是癌症死亡的第二大原因。明确的诊断是基于系统的经直肠超声(TRUS)引导的前列腺活检，通常是由于前列腺特异性抗原(PSA)筛查的广泛使用。然而，这种方法漏掉了大约40%的前列腺癌，导致重复活检，患者发病率和医疗保健成本都很高。因此，有一个尚未满足的迫切需要，影像引导活检，以最大限度地发现临床相关肿瘤的可能性，以避免目前对致命性肿瘤的诊断不足(和治疗不足)，以及反过来对惰性肿瘤的过度诊断(和过度治疗)。图像引导下的前列腺癌的检测和定性将为制定合理的治疗策略铺平道路，包括对器官受限的高级别肿瘤的新兴的局部治疗。据报道，多参数磁共振成像(MpMRI)为前列腺癌的检测提供了相对较高的特异性和可变的敏感性。各种示踪剂的正电子发射断层扫描(PET)的潜在用途主要集中在疾病的生化复发和抗去势转移阶段。目前，对于可疑前列腺癌患者的原发灶的准确检测、定位和定性，特别是在最初的阴性标准TRUS引导活检后，缺乏任何与PET示踪剂相关的数据。我们对细胞增殖和细胞应激生物标记物18F-2‘-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil(18F-FMAU)的合成和评价与正电子发射计算机断层扫描有着长期的兴趣和经验。我们的努力包括完成R21资助的18F-FMAU在前列腺癌动物模型中的临床前评估，自上次审查以来，获得了足够的资金，用于一名患者的IRB-RDRC批准的概念验证临床病例研究，以及最近向美国食品和药物管理局提交的研究性新药申请。我们现在处于战略地位，可以继续沿着这条研究路线进行更多的以人为基础的可行性试验试点。因此，这个修订的R21提案的目的是对怀疑为前列腺癌的男性进行系统的18F-FMAU研究，以便在最初诊断时发现、定位和表征原发肿瘤。这项建议的两个具体目的是：1)对40名前列腺癌患者进行前瞻性的临床影像评估，根据前列腺癌特异性抗原水平升高或升高，18F-FMAU PET/CT检测和定位原发癌，包括那些计划接受临床mpMRI和TRUS引导活检的患者；2)研究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的关系。基本的假设是18F-FMAU在原发性前列腺癌中积聚，从而允许图像导向活检，摄取水平反映了肿瘤增殖指数。我们认为，18F-FMAU PET/CT结合mpMRI引导的前列腺活检将显著改善现状，并影响对疑似前列腺癌男性的诊断评估。

 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.