Clinical Evaluation of a Novel Prostate Cancer PET Diagnostic

描述(申请人提供)：前列腺癌(PCa)是美国男性最常见的癌症，也是导致癌症死亡的第二大原因。被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%的前列腺癌患者的PSA水平在当前的PSA参考范围内。升高的PSA水平与前列腺癌的分期没有很好的相关性，相当数量的男性暴露在不必要的手术和放射治疗中，伴随着风险和有害的副作用。前列腺癌的分子成像在疾病的诊断、分期和治疗中发挥着越来越重要的作用。然而，自1996年以来，FDA只批准了一种用于前列腺癌的诊断试剂，ProstaScint，一种鼠单抗。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”结合了细胞内的表位，使其无法检测活的前列腺癌细胞。因此，不到50%的诊断准确率导致肿瘤学家对这种成像测试的采用不佳。PSMA是一种跨膜蛋白，已被认为是一种理想的前列腺癌诊断和靶向治疗的生物标志物，因为它1)主要在前列腺癌中表达，发病率为90%；2)在疾病的各个阶段都有高表达，在雄激素不敏感和转移的疾病中表达上调；3)可在细胞表面获得，不进入循环；4)在配体结合后内化。为了满足对PCA准确和定量成像的需求，我们将推出我们的新型、专有、低分子量PSMA抑制剂，它可以选择性地将成像放射性核素输送到PCA细胞。这种小分子抑制剂CTT1057在IC50小于1 NM时不可逆地与PSMA结合。此外，CTT1057及其18F成像有效载荷在不到30分钟内被内化到PSMA表达细胞中。这种不可逆转的结合和快速内化使该分子在开发中的PSMA抑制剂中独一无二，并允许良好的生物分布和肿瘤摄取。此外，我们正在寻求使用18F标记的放射性示踪剂的PET(相对于SPECT)更灵敏和定量的诊断成像方式。在这笔赠款中，我们将通过在AIM 1完成cGMP制造和I期临床材料的自动放射性标记来推动我们的PET显像剂CTT1057的开发。在AIM 2中，我们将在0/I期临床试验中建立人体安全概况，可视化PCA病变并确定最佳成像参数和剂量学。使用我们的18F标记的PSMA抑制剂CTT1057的PET成像将允许快速和灵敏地评估PCa的近端和远端表现，这是目前无法获得的。

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.