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

Lynn G Feun, A. Marini, G. Walker, George Elgart, Frederick L Moffat, Steven Rodgers, C. J. Wu, M. You, Medhi Wangpaichitr, M. T. Kuo, W. Sisson, A. A. Jungbluth, J. Bomalaski, Niramol Savaraj

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Abstract

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 IU m -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.

Original languageEnglish
Pages (from-to)1481-1485
Number of pages5
JournalBritish Journal of Cancer
Volume106
Issue number9
DOIs
StatePublished - Apr 24 2012

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Argininosuccinate Synthase
Arginine
Melanoma
Neoplasms
Therapeutics
ADI PEG20

Keywords

  • arginine
  • arginine deiminase
  • Melanoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase. / Feun, Lynn G; Marini, A.; Walker, G.; Elgart, George; Moffat, Frederick L; Rodgers, Steven; Wu, C. J.; You, M.; Wangpaichitr, Medhi; Kuo, M. T.; Sisson, W.; Jungbluth, A. A.; Bomalaski, J.; Savaraj, Niramol.

In: British Journal of Cancer, Vol. 106, No. 9, 24.04.2012, p. 1481-1485.

Research output: Contribution to journalArticle

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title = "Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase",
abstract = "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 IU m -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.",
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T1 - Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase

AU - Feun, Lynn G

AU - Marini, A.

AU - Walker, G.

AU - Elgart, George

AU - Moffat, Frederick L

AU - Rodgers, Steven

AU - Wu, C. J.

AU - You, M.

AU - Wangpaichitr, Medhi

AU - Kuo, M. T.

AU - Sisson, W.

AU - Jungbluth, A. A.

AU - Bomalaski, J.

AU - Savaraj, Niramol

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N2 - 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 IU m -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.

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