Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase

被引:92
作者
Feun, L. G. [1 ]
Marini, A. [1 ]
Walker, G. [1 ]
Elgart, G. [1 ]
Moffat, F. [1 ]
Rodgers, S. E. [1 ]
Wu, C. J. [1 ]
You, M. [1 ]
Wangpaichitr, M. [1 ]
Kuo, M. T. [2 ]
Sisson, W. [3 ]
Jungbluth, A. A. [4 ]
Bomalaski, J. [3 ]
Savaraj, N. [1 ]
机构
[1] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA
[2] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
[3] Polaris Grp, San Diego, CA 92121 USA
[4] Mem Sloan Kettering Canc Ctr, Ludwig Inst Canc Res, New York, NY 10021 USA
关键词
melanoma; arginine; arginine deiminase; IN-VIVO; ANTITUMOR-ACTIVITY; CELL-LINES; DEPRIVATION; CANCER; CARCINOMA; APOPTOSIS; AUTOPHAGY;
D O I
10.1038/bjc.2012.106
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BACKGROUND: Arginine-depleting therapy with pegylated arginine deiminase (ADI-PEG20) was reported to have activity in advanced melanoma in early phase I-II trial, and clinical trials are currently underway in other cancers. However, the optimal patient population who benefit from this treatment is unknown. METHODS: Advanced melanoma patients with accessible tumours had biopsy performed before the start of treatment with ADI-PEG20 and at the time of progression or relapse when amenable to determine whether argininosuccinate synthetase (ASS) expression in tumour was predictive of response to ADI-PEG20. RESULTS: Twenty-seven of thirty-eight patients treated had melanoma tumours assessable for ASS staining before treatment. Clinical benefit rate (CBR) and longer time to progression were associated with negative expression of tumour ASS. Only 1 of 10 patients with ASS-positive tumours (ASS+) had stable disease, whereas 4 of 17 (24%) had partial response and 5 had stable disease, when ASS expression was negative (ASS-), giving CBR rates of 52.9 vs 10%, P = 0.041. Two responding patients with negative ASS expression before therapy had rebiopsy after tumour progression and the ASS expression became positive. The survival of ASS - patients receiving at least four doses at 320 IUm(-2) was significantly better than the ASS+ group at 26.5 vs 8.5 months, P = 0.024. CONCLUSION: ADI-PEG20 is safe and the drug is only efficacious in melanoma patients whose tumour has negative ASS expression. Argininosuccinate synthetase tumour positivity is associated with drug resistance and tumour progression. British Journal of Cancer (2012) 106, 1481-1485. doi:10.1038/bjc.2012.106 www.bjcancer.com Published online 3 April 2012 (C) 2012 Cancer Research UK
引用
收藏
页码:1481 / 1485
页数:5
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