ABT-888 confers broad in vivo activity in combination with temozolomide in diverse tumors.
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.
Palma
Joann P
JP
Abbott Laboratories, Cancer Research, Abbott Park, Illinois 60064, USA.
Wang
Yi-Chun
YC
Rodriguez
Luis E
LE
Montgomery
Debra
D
Ellis
Paul A
PA
Bukofzer
Gail
G
Niquette
Amanda
A
Liu
Xuesong
X
Shi
Yan
Y
Lasko
Loren
L
Zhu
Gui-Dong
GD
Penning
Thomas D
TD
Giranda
Vincent L
VL
Rosenberg
Saul H
SH
Frost
David J
DJ
Donawho
Cherrie K
CK
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
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