title: ABT-888 confers broad in vivo activity in combination with temozolomide in diverse tumors.
abstract: OBJECTIVE
  ABT-888, currently in phase 2 trials, is a potent oral poly(ADP-ribose) polymerase inhibitor that enhances the activity of multiple DNA-damaging agents, including temozolomide (TMZ). We investigated ABT-888+TMZ combination therapy in multiple xenograft models representing various human tumors having different responses to TMZ.
  
  
  METHODS
  ABT-888+TMZ efficacy in xenograft tumors implanted in subcutaneous, orthotopic, and metastatic sites was assessed by tumor burden, expression of poly(ADP-ribose) polymer, and O(6)-methylguanine methyltransferase (MGMT).
  
  
  RESULTS
  Varying levels of ABT-888+TMZ sensitivity were evident across a broad histologic spectrum of models (55-100% tumor growth inhibition) in B-cell lymphoma, small cell lung carcinoma, non-small cell lung carcinoma, pancreatic, ovarian, breast, and prostate xenografts, including numerous regressions. Combination efficacy in otherwise TMZ nonresponsive tumors suggests that TMZ resistance may be overcome by poly(ADP-ribose) polymerase inhibition. Profound ABT-888+TMZ efficacy was seen in experimental metastases models that acquired resistance to TMZ. Moreover, TMZ resistance was overcome in crossover treatments, indicating that combination therapy may overcome acquired TMZ resistance. Neither tumor MGMT, mismatch repair, nor poly(ADP-ribose) polymer correlated with the degree of sensitivity to ABT-888+TMZ.
  
  
  CONCLUSIONS
  Robust ABT-888+TMZ efficacy is observed across a spectrum of tumor types, including orthotopic and metastatic implantation. As many TMZ nonresponsive tumors proved sensitive to ABT-888+TMZ, this novel combination may broaden the clinical use of TMZ beyond melanoma and glioma. Although TMZ resistance may be influenced by MGMT, neither MGMT nor other mechanisms of TMZ resistance (mismatch repair) precluded sensitivity to ABT-888+TMZ. Underlying mechanisms of TMZ resistance in these models are not completely understood but likely involve mechanisms independent of MGMT.
authors.affiliation: Abbott Laboratories, Cancer Research, Abbott Park, Illinois 60064, USA.
authors.forename: Joann P
authors.initials: JP
authors.lastname: Palma
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: Luis E
authors.initials: LE
authors.lastname: Rodriguez
authors.forename: Debra
authors.initials: D
authors.lastname: Montgomery
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ellis
authors.forename: Gail
authors.initials: G
authors.lastname: Bukofzer
authors.forename: Amanda
authors.initials: A
authors.lastname: Niquette
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Loren
authors.initials: L
authors.lastname: Lasko
authors.forename: Gui-Dong
authors.initials: GD
authors.lastname: Zhu
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Penning
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: David J
authors.initials: DJ
authors.lastname: Frost
authors.forename: Cherrie K
authors.initials: CK
authors.lastname: Donawho
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage*; D004249:DNA Damage; D015254:DNA Modification Methylases / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D025521:Tumor Suppressor Proteins; C521013:veliparib; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide