Poor Diagnostic Performance of the Melanin-Binding Tracer [18 F]MEL050 in Human Melanoma Indicates Biological Heterogeneity.

IF 2.5 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Molecular Imaging and Biology Pub Date : 2025-08-01 Epub Date: 2025-06-19 DOI:10.1007/s11307-025-02025-0

Robert E Ware, Damien Kee, Peter Roselt, Ivan Greguric, Andrew Katsifis, Thomas Bourdier, Wayne Noonan, William Murray, Catherine Mitchell, Marnie Downes, Mark Shackleton, Grant A McArthur, Rodney J Hicks

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引用次数: 0

Abstract

Purpose: Malignant melanoma is a highly lethal malignancy typically characterized by the expression of melanin, which is an attractive diagnostic and therapeutic target in these cancers because it is expressed in few other tissues. Following preclinical evaluation of the melanin-targeting PET tracer, [18F]-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide ([18F]MEL050), we sought to evaluate this agent in patients with melanoma.

Method: A phase I clinical trial was performed in ten patients with metastatic melanoma. Safety, dosimetry and diagnostic performance of intravenously administered][18F]MEL050 were evaluated. Based on results from this trial, we further assessed the prevalence and prognostic significance of loss of melanin expression in two historical patient cohorts for which there were matching histological and clinical outcome data.

Results: Across the trial cohort, no adverse safety signals resulted from [18F]MEL050 administration. The whole-body effective dose was 0.0163 mSV/MBq for an adult male and 0.0206 mSV/MBq for an adult female. The human biodistribution was favorable with low uptake in organs at high risk of metastatic spread, including the brain. Of metastatic sites identified as melanoma on [18F]FDG PET/CT, only 31/65 (48%) were positive on [18F]MEL050 PET. Four [18F]FDG+[18F]MEL050+ metastases were resected from three patients and found to be melanotic by histological examination, whereas five [18F]FDG+[18F]MEL050- metastases from two patients were amelanotic. In our historical cohorts, amelanosis was more common in metastatic than primary disease (45% versus 20%) and the presence of melanin within sentinel lymph node metastases was associated with worse disease-free (HR 2.3 95% CI 1.3 - 4.3, p = 0.002) and disease-specific survivals (HR 3.6, 95% CI 1.4 - 9.7,p = 0.009) in stage III disease, compared with amelanotic sentinel lymph node metastases.

Conclusion: We propose caution in the use of melanin-targeted agents for melanoma diagnosis and therapy until their utility as prognostic or predictive imaging biomarkers, and the biological implications of loss of melanin deposition during melanoma progression, are better understood.

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黑色素结合示踪剂MEL050在人类黑色素瘤中的诊断性能较差表明生物异质性。

目的：恶性黑色素瘤是一种高度致死性的恶性肿瘤，其典型特征是黑色素的表达，黑色素在这些癌症中是一个有吸引力的诊断和治疗靶点，因为它在少数其他组织中表达。在对黑色素靶向PET示踪剂[18F]-6-氟- n-[2-（二乙基氨基）乙基]吡啶-3-羧酰胺（[18F]MEL050）进行临床前评估后，我们试图评估该药物在黑色素瘤患者中的作用。方法：在10例转移性黑色素瘤患者中进行I期临床试验。对静脉给药[18F]MEL050的安全性、剂量学和诊断性能进行评价。基于该试验的结果，我们进一步评估了两个具有匹配组织学和临床结果数据的历史患者队列中黑色素表达缺失的患病率和预后意义。结果：在整个试验队列中，服用[18F]MEL050后未出现不良安全信号。成年男性和成年女性的全身有效剂量分别为0.0163 mSV/MBq和0.0206 mSV/MBq。人体生物分布有利，在转移扩散风险高的器官（包括大脑）中吸收低。在[18F]FDG PET/CT鉴定为黑色素瘤的转移部位中，只有31/65（48%）在[18F]MEL050 PET上呈阳性。3例患者的4例[18F]FDG+[18F]MEL050+转移瘤经组织学检查为黑色素瘤，2例患者的5例[18F]FDG+[18F]MEL050-转移瘤为无色素瘤。在我们的历史队列中，无色素变性在转移性疾病中比原发疾病更常见（45%对20%），与无色素变性前哨淋巴结转移相比，在III期疾病中，前哨淋巴结转移中黑色素的存在与更差的无病生存率（HR 2.3 95% CI 1.3 - 4.3, p = 0.002）和疾病特异性生存率（HR 3.6, 95% CI 1.4 - 9.7,p = 0.009）相关。结论：我们建议在黑色素靶向药物用于黑色素瘤的诊断和治疗时要谨慎，直到它们作为预后或预测成像生物标志物的效用，以及黑色素瘤进展过程中黑色素沉积损失的生物学意义得到更好的理解。

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来源期刊

Molecular Imaging and Biology 医学-核医学

CiteScore

6.90

自引率

3.20%

发文量

审稿时长

3 months

期刊介绍： Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures. Some areas that are covered are: Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes. The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets. Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display. Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging. Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics. Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations. Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.