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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, FL 33136, USA. lfeun@med.miami.edu
authors.forename: L G
authors.initials: LG
authors.lastname: Feun
authors.forename: A
authors.initials: A
authors.lastname: Marini
authors.forename: G
authors.initials: G
authors.lastname: Walker
authors.forename: G
authors.initials: G
authors.lastname: Elgart
authors.forename: F
authors.initials: F
authors.lastname: Moffat
authors.forename: S E
authors.initials: SE
authors.lastname: Rodgers
authors.forename: C J
authors.initials: CJ
authors.lastname: Wu
authors.forename: M
authors.initials: M
authors.lastname: You
authors.forename: M
authors.initials: M
authors.lastname: Wangpaichitr
authors.forename: M T
authors.initials: MT
authors.lastname: Kuo
authors.forename: W
authors.initials: W
authors.lastname: Sisson
authors.forename: A A
authors.initials: AA
authors.lastname: Jungbluth
authors.forename: J
authors.initials: J
authors.lastname: Bomalaski
authors.forename: N
authors.initials: N
authors.lastname: Savaraj
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000172:deficiency*; D001124:Argininosuccinate Synthase / Q000378:metabolism*; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C512527:ADI PEG20; D001124:Argininosuccinate Synthase