Carbon-11 Labeled Sarcosine: Mechanism of Action and Initial Performance in Prostate Cancer

 描述(申请人提供)：目前前列腺癌(PCA)的成像性能不能令人满意。临床医生需要一种诊断成像方法来揭示PCa的主要位置、临床意义和预测其恶性潜能。此外，在确诊治疗后，往往很难发现复发的疾病，这阻碍了有效的局部抢救治疗。此外，考虑到转移性前列腺癌的新的全身治疗选择，早期(通过成像)选择治疗方案和监测治疗成功可能会使患者受益，并通过避免无效的全身治疗来降低成本。利用代谢组学分析，肌氨酸水平在原发性前列腺癌组织中升高，并在前列腺癌进展过程中进一步升高。我们的临床前数据显示，在前列腺癌肿瘤模型中，含有11C-肌氨酸的微型PET的效果优于11C-胆碱。基于这些令人鼓舞的数据，我们假设11C-肌氨酸PET成像能够识别原发和转移性前列腺癌，用于人类的分期和反应评估。本研究的目标是利用11C-肌氨酸作为前列腺癌的PET示踪剂进行初步试验，并评价11C-肌氨酸在人前列腺癌组织中的摄取机制和代谢途径。目的：(1)开发人用11C-肌氨酸作为PET示踪剂；(2)对前列腺癌患者进行11C-肌氨酸的初步研究，以收集初步疗效并评估其可行性；(3)测量11C-肌氨酸的人体辐射剂量学；(4)评估人前列腺癌组织中肌氨酸摄取的调节。研究设计：目前生产的11C-肌氨酸将根据GMP标准进行修改(目标1)。为了评估目标2，人类前列腺癌受试者将接受11C-肌氨酸和11C-胆碱的PET/CT成像，以直接比较生物分布和肿瘤摄取。这项研究将包括接受前列腺癌切除术(A组)和复发和/或转移性疾病(B组)的前列腺癌患者。11C-肌氨酸的人体辐射剂量学测定是在正常志愿者身上进行的(目标3)。对于AIM 4，肿瘤组织样本将接受基于液体和气相色谱-质谱学技术的标准病理和目标代谢物分析，以专门评估前列腺癌中肌氨酸的代谢途径，并与11C-肌氨酸摄取测量进行比较。影响：如果成功，这项研究将导致一种新的前列腺癌分子成像策略，将前列腺癌与正常良性组织区分开来，并克服目前在前列腺癌治疗分期和监测方面的局限性。

 DESCRIPTION (provided by applicant): The performance of current prostate cancer (PCa) imaging is unsatisfactory. Clinicians need a diagnostic imaging approach that reveals primary PCa location, its clinical significance and predicts its malignant potential. Furthermore, the detection of recurrent disease is often difficult after definitive treatment, hampering effective local salvage treatments. Also given new systemic treatment option in metastatic PCa, the selection of treatment options and monitoring of treatment success early (via imaging) may benefit patients and reduce costs by avoiding ineffective systemic treatments. Using metabolomic profiling, tissue levels of sarcosine have been identified to be elevated in primary PCa with further increase during PCa progression. Our preclinical data show that micro-PET with 11C- sarcosine outperforms 11C-choline in prostate cancer tumor models. Based on these encouraging data, we hypothesize that PET imaging with 11C-sarcosine is able to identify primary and metastatic PCa for staging and response evaluation in humans. The study goals are to conduct a pilot trial using 11C- sarcosine as PET tracer for PCa and to evaluate the uptake mechanisms and metabolic pathways of 11C-sarcosine in human PCa tissue. Objectives: (1) Development of 11C-sarcosine as PET tracer for human use, (2) conduction of a pilot study with 11C-sarcosine in human prostate cancer subjects to collect preliminary efficacy and to assess feasibility, (3) measurement of the human radiation dosimetry of 11C-sarcosine, and (4) assessment of sarcosine uptake regulation in human prostate cancer tissue samples. Study design: The current 11C-sarcosine production will be modified according to GMP standards (aim 1). To assess aim 2, human prostate cancer subjects will undergo PET/CT imaging with 11C-sarcosine and 11C-choline to directly compare biodistribution and tumor uptake. The study will include PCa subjects undergoing prostatectomy (group A) and recurrent and/or metastatic disease (group B). The human radiation dosimetry of 11C-sarcosine is determined in normal volunteers (aim 3). For aim 4, tumor tissue samples will undergo standard pathology and target metabolite analysis based on liquid-and-gas- chromatography mass spectrometry techniques to specifically assess the metabolic pathways for sarcosine in prostate cancer and to compare these with 11C-sarcosine uptake measurements. Impact: If successful, this study would lead to a novel molecular imaging strategy for PCa, differentiating PCa from normal benign tissues, and overcome current limitation in staging and monitoring prostate cancer treatments.