title: Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma.
abstract: PR-104 is a clinical stage bioreductive prodrug that is converted in vivo to its cognate alcohol, PR-104A. This dinitrobenzamide mustard is reduced to activated DNA cross-linking metabolites (hydroxylamine PR-104H and amine PR-104M) under hypoxia by one-electron reductases and independently of hypoxia by the 2-electron reductase aldo-keto reductase 1C3 (AKR1C3). High expression of AKR1C3, along with extensive hypoxia, suggested the potential of PR-104 for treatment of hepatocellular carcinoma (HCC). However, a phase IB trial with sorafenib demonstrated significant toxicity that was ascribed in part to reduced PR-104A clearance, likely reflecting compromised glucuronidation in patients with advanced HCC. Here, we evaluate the activity of PR-104 in HCC xenografts (HepG2, PLC/PRF/5, SNU-398, Hep3B) in mice, which do not significantly glucuronidate PR-104A. Cell line differences in sensitivity to PR-104A in vitro under aerobic conditions could be accounted for by differences in both expression of AKR1C3 (high in HepG2 and PLC/PRF/5) and sensitivity to the major active metabolite PR-104H, to which PLC/PRF/5 was relatively resistant, while hypoxic selectivity of PR-104A cytotoxicity and reductive metabolism was greatest in the low-AKR1C3 SNU-398 and Hep3B lines. Expression of AKR1C3 in HepG2 and PLC/PRF/5 xenografts was in the range seen in 21 human HCC specimens. PR-104 monotherapy elicited significant reductions in growth of Hep3B and HepG2 xenografts, and the combination with sorafenib was significantly active in all 4 xenograft models. The results suggest that better-tolerated analogs of PR-104, without a glucuronidation liability, may have the potential to exploit AKR1C3 and/or hypoxia in HCC in humans.
authors: a Auckland Cancer Society Research Centre; School of Medical Sciences.
authors: Maria R
authors: MR
authors: Abbattista
authors: Stephen M F
authors: SM
authors: Jamieson
authors: Yongchuan
authors: Y
authors: Gu
authors: Jennifer E
authors: JE
authors: Nickel
authors: Susan M
authors: SM
authors: Pullen
authors: Adam V
authors: AV
authors: Patterson
authors: William R
authors: WR
authors: Wilson
authors: Christopher P
authors: CP
authors: Guise
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D009588:Nitrogen Mustard Compounds; C524170:PR-104A; D010671:Phenylurea Compounds; D011355:Prodrugs; D009536:Niacinamide; D000077157:Sorafenib
keywords: AKR1C3; AKR1C3, aldo-keto reductase 1C3; HCC, hepatocellular carcinoma; HCR, hypoxic cytotoxicity ratio; Hypoxia; Nrf2, NF-E2-related factor-2; POR, NADPH:cytochrome P450 oxidoreductase; PR-104; UGT-2B7, UDP-glucuronosyltransferase-2B7; hepatocellular carcinoma; hypoxia-activated prodrugs; nitrogen mustards; sorafenib