Clinical Evaluation of a Novel Prostate Cancer PET Diagnostic

描述（由申请人提供）：前列腺癌（PCa）是美国男性中最常诊断的癌症，也是癌症死亡的第二大原因。广泛接受的前列腺癌诊断测试PSA测试的实用性受到了严格的审查，因为只有20-30%的前列腺癌男性的水平在目前的PSA参考范围内。升高的PSA水平与PCa的阶段没有很好的相关性，并且相当数量的男性暴露于不必要的手术和放射治疗，伴随着风险和有害的副作用。前列腺癌的分子影像学是一个越来越重要的组成部分，诊断，分期和治疗疾病。然而，自1996年以来，FDA仅批准了一种PCa诊断剂，即小鼠单克隆抗体ProstaScint。虽然ProstaScint识别的标志物，前列腺特异性膜抗原（PSMA），是理想的生物标志物，但ProstaScint结合细胞内表位，使其无法检测活的PCa细胞。因此，低于50%的诊断准确性导致肿瘤学家对这种成像测试的采用率很低。PSMA是一种跨膜蛋白，已被描述为PCa诊断和靶向治疗的理想生物标志物，因为它1）主要在PCa中表达，患病率> 90%，2）在疾病的所有阶段具有高表达水平，并且在雄激素不敏感和转移性疾病中上调，3）在细胞表面上可接近，并且不脱落到循环中，和4）在配体结合后内化。为了解决PCa准确和定量成像的未满足需求，我们将推进我们的新型，专有，低分子量PSMA抑制剂，选择性地将成像放射性核素递送到PCa细胞。这种小分子抑制剂CTT 1057以小于1 nM的IC 50不可逆地结合PSMA。此外，CTT 1057及其18F成像有效载荷在不到30分钟内内化到表达PSMA的细胞中。这种不可逆的结合和快速内化使得这种分子在正在开发的PSMA抑制剂中是独特的，并且允许优异的生物分布和肿瘤摄取。此外，我们正在寻求更敏感和定量的诊断成像方式的PET（而不是SPECT）使用18 F标记的放射性示踪剂。在这项资助中，我们将通过完成目标1中I期临床材料的cGMP生产和自动化放射性标记来推进PET显像剂CTT 1057的开发。在目标2中，我们将在PCa患者的0/I期临床试验中建立人体安全性特征以及可视化PCa病变并确定最佳成像参数和剂量测定。使用我们的18F标记的PSMA抑制剂CTT 1057的PET成像将允许对PCa的近端和远端表现进行快速和灵敏的评估，这是目前不可用的。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of cancer death in American men. The utility of the widely accepted diagnostic test for PCa, the PSA test, has come under severe scrutiny as only 20-30% of men with PCa have levels that fall within the current PSA reference range. Elevated PSA levels are not correlated well with the stage of PCa and a significant number of men are exposed to unnecessary surgery and radiation therapy with concomitant risks and detrimental side effects. Molecular imaging of PCa is an increasingly important component for diagnosis, staging and treatment of the disease. However, the FDA has approved only one diagnostic agent for PCa since 1996, ProstaScint", a mouse monoclonal antibody. While the marker that ProstaScint" recognizes, prostate-specific membrane antigen (PSMA), is ideal as a biomarker, ProstaScint" binds an intracellular epitope, rendering it unable to detect living PCa cells. As a result, diagnostic accuracy of less than 50% has led to poor adoption of this imaging test by oncologists. PSMA, a transmembrane protein, has been described as an ideal biomarker for PCa diagnosis and targeted therapy as it 1) is expressed mainly in PCa with a prevalence of >90%, 2) has high expression levels at all stages of the disease and is upregulated in androgen-insensitive and metastatic disease, 3) is accessible on the cell surface and not shed into the circulation, and 4) is internalized after ligand binding. To address the unmet need for accurate and quantitative imaging of PCa we will advance our novel, proprietary, low molecular weight PSMA inhibitor that selectively delivers an imaging radionuclide to PCa cells. This small molecule inhibitor, CTT1057, binds PSMA irreversibly at an IC50 of less than 1 nM. In addition, CTT1057 and its 18F imaging payload is internalized into PSMA expressing cells in less than 30 minutes. This irreversible binding and rapid internalization makes this molecule unique amongst PSMA inhibitors that are in development and allows for excellent biodistribution and tumor uptake. In addition, we are pursuing the more sensitive and quantitative diagnostic imaging modality of PET (as opposed to SPECT) using a 18F-labeled radiotracer. In this grant we will advance the development of our PET imaging agent CTT1057 by completing the cGMP manufacture and automated radiolabeling of Phase I clinical material in Aim 1. In Aim 2, we will establish a human safety profile as well as visualize PCa lesions and determine optimal imaging parameters and dosimetry in a Phase 0/I clinical trial in PCa patients. PET imaging using our 18F-labeled PSMA inhibitor CTT1057 will allow for rapid and sensitive assessment of proximal and distal manifestations of PCa, something which is currently unavailable.