Zhang Tian, Kephart Julie, Bronson Elizabeth, Anand Monika, Daly Christine, Spasojevic Ivan, Bakthavatsalam Subha, Franz Katherine, Berg Hannah, Karachaliou Georgia S, James Olga G, Howard Lauren, Halabi Susan, Harrison Michael R, Armstrong Andrew J, George Daniel J
Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina, USA.
Division of Medical Oncology, Department of Medicine, Duke University, Durham, North Carolina, USA.
Prostate. 2022 May;82(7):858-866. doi: 10.1002/pros.24329. Epub 2022 Mar 14.
In preclinical models of prostate cancer (PC), disulfiram (DSF) reduced tumor growth only when co-administered with copper (Cu), and Cu uptake in tumors is partially regulated by androgen-receptor signaling. However, prior trials of DSF in PC used DSF as monotherapy.
To assess the safety and efficacy of concurrent administration of DSF with Cu, we conducted a phase 1b clinical trial of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Cu with DSF.
DESIGN, SETTING, AND PARTICIPANTS: Patients with mCRPC were treated in two cohorts: mCRPC with nonliver/peritoneal metastases (A), and mCRPC with liver and/or peritoneal metastases (B). Baseline Cu avidity was measured by CuCl PET scan. Intravenous (IV) CuCl was given weekly for three doses with oral daily DSF followed by daily oral Cu gluconate and DSF until disease progression. DSF and metabolite diethyldithiocarbamic acid methyl ester (Me-DDC) levels in plasma were measured. DSF and Me-DDC were then assessed for cytotoxicity in vitro.
We treated nine patients with mCRPC (six on cohort A and three on cohort B). Bone and nodal metastases showed differential and heterogeneous Cu uptake on CuCl PET scans. No confirmed PSA declines or radiographic responses were observed. Median PFS was 2.8 months and median OS was 8.3 months. Common adverse events included fatigue and psychomotor depression; no Grade 4/5 AEs were observed. Me-DDC was measurable in all samples (LOQ = 0.512 ng/ml), whereas DSF was not (LOQ = 0.032 ng/ml, LOD = 0.01 ng/ml); Me-DDC was not cytotoxic in vitro.
Oral DSF is not an effective treatment for mCRPC due to rapid metabolism into an inactive metabolite, Me-DDC. This trial has stopped enrollment and further work is needed to identify a stable DSF formulation for treatment of mCRPC.
在前列腺癌（PC）的临床前模型中，双硫仑（DSF）仅在与铜（Cu）共同给药时才会降低肿瘤生长，并且肿瘤中的铜摄取部分受雄激素受体信号传导调节。然而，先前在PC中进行的DSF试验使用DSF作为单一疗法。
为了评估DSF与Cu联合给药的安全性和有效性，我们对接受Cu与DSF治疗的转移性去势抵抗性前列腺癌（mCRPC）患者进行了1b期临床试验。
设计、设置和参与者：mCRPC患者分为两个队列进行治疗：非肝脏/腹膜转移的mCRPC（A组）和有肝脏和/或腹膜转移的mCRPC（B组）。通过氯化铜PET扫描测量基线铜亲和力。静脉注射（IV）氯化铜每周给药3剂，同时每日口服DSF，随后每日口服葡萄糖酸铜和DSF，直至疾病进展。测量血浆中DSF和代谢物二乙二硫代氨基甲酸甲酯（Me-DDC）的水平。然后评估DSF和Me-DDC在体外的细胞毒性。
我们治疗了9例mCRPC患者（A组6例，B组3例）。在氯化铜PET扫描中，骨和淋巴结转移显示出不同且异质的铜摄取。未观察到确诊的PSA下降或影像学反应。中位无进展生存期为2.8个月，中位总生存期为8.3个月。常见的不良事件包括疲劳和精神运动性抑郁；未观察到4/5级不良事件。所有样本中均可检测到Me-DDC（定量限=0.512 ng/ml），而DSF未检测到（定量限=0.032 ng/ml，检测限=0.01 ng/ml）；Me-DDC在体外无细胞毒性。
口服DSF由于迅速代谢为无活性代谢物Me-DDC，因此不是mCRPC的有效治疗方法。该试验已停止入组，需要进一步开展工作以确定用于治疗mCRPC的稳定DSF制剂。
