Immunohistochemical detection of poly(ADP-ribose) polymerase inhibition by ABT-888 in patients with refractory solid tumors and lymphomas.
OBJECTIVE
Targeting the poly (ADP-ribose) polymerase (PARP) pathway for cancer treatment has been an active area of pre-clinical and clinical research. We aimed to determine whether the PARP inhibitor ABT-888 hits its therapeutic target in tumors by immunohistochemistry during a Phase 0 trial conducted at the National Cancer Institute.


METHODS
The expression of poly (ADP-ribose) (PAR) and full size PARP-1 were quantitatively examined by immunohistochemistry in paraffin-embedded tumor biopsies at baseline and 3-24 h after a single oral dose (25 or 50 mg) of ABT-888.


RESULTS
Baseline PAR levels were moderate to high in three patients with non-Hodgkin lymphomas, and one each with small cell lung cancer, squamous cell carcinoma of the tongue and melanoma; low in two patients with cutaneous T-cell lymphoma and one with adenocarcinoma of external ear canal. A significant decrease in PAR (median decrease 30.2, range -13.1 to -69.8) was achieved after drug administration (n = 6 pairs; p = 0.03), whereas an increase in PARP-1 expression was observed in five of the six tumors. This resulted in a decrease in the ratio of PAR to PARP-1 in tumor biopsies (median -6.76, range -0.41 to -22.59; p = 0.03).


CONCLUSIONS
ABT-888 hits its therapeutic target by significantly reducing PAR levels and the ratio of PAR to PARP-1 in human tumor cells detected by immunohistochemistry. Baseline tumor PAR levels vary considerably among patients who entered this phase 0 study. This underscores a need to investigate baseline PAR levels in association with response in future preclinical and clinical studies.
Yang
Sherry X
SX
Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA. yangxia@mail.nih.gov
Kummar
Shivaani
S
Steinberg
Seth M
SM
Murgo
Anthony J
AJ
Gutierrez
Martin
M
Rubinstein
Larry
L
Nguyen
Dat
D
Kaur
Gurmeet
G
Chen
Alice P
AP
Giranda
Vincent L
VL
Tomaszewski
Joseph E
JE
Doroshow
James H
JH
D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008223:Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases