TY - JOUR
T1 - Prospective clinical trial of disulfiram plus copper in men with metastatic castration-resistant prostate cancer
AU - Zhang, Tian
AU - Kephart, Julie
AU - Bronson, Elizabeth
AU - Anand, Monika
AU - Daly, Christine
AU - Spasojevic, Ivan
AU - Bakthavatsalam, Subha
AU - Franz, Katherine
AU - Berg, Hannah
AU - Karachaliou, Georgia S.
AU - James, Olga G.
AU - Howard, Lauren
AU - Halabi, Susan
AU - Harrison, Michael R.
AU - Armstrong, Andrew J.
AU - George, Daniel J.
N1 - Publisher Copyright:
© 2022 Wiley Periodicals LLC.
PY - 2022/5/15
Y1 - 2022/5/15
N2 - Background: 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. Objective: 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 64CuCl2 PET scan. Intravenous (IV) CuCl2 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. Results: 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 64CuCl2 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. Conclusions: 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.
AB - Background: 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. Objective: 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 64CuCl2 PET scan. Intravenous (IV) CuCl2 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. Results: 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 64CuCl2 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. Conclusions: 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.
KW - copper PET imaging (64CuCl2 PET)
KW - diethyldithiocarbamic Acid Methyl Ester (Me-DDC)
KW - disulfiram (DSF)
KW - metastatic castration-resistant prostate cancer (mCRPC)
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U2 - 10.1002/pros.24329
DO - 10.1002/pros.24329
M3 - Article
C2 - 35286730
AN - SCOPUS:85126243287
SN - 0270-4137
VL - 82
SP - 858
EP - 866
JO - Prostate
JF - Prostate
IS - 7
ER -