Immunohistochemical detection of poly(ADP-ribose) polymerase inhibition by ABT-888 in patients with refractory solid tumors and lymphomas

Sherry X. Yang, Shivaani Kummar, Seth M. Steinberg, Anthony J. Murgo, Martin Gutierrez, Larry Rubinstein, Dat Nguyen, Gurmeet Kaur, Alice P. Chen, Vincent L. Giranda, Joseph E. Tomaszewski, James H. Doroshow

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Purpose: 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. experimental design: 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.

Original languageEnglish (US)
Pages (from-to)2004-2009
Number of pages6
JournalCancer Biology and Therapy
Volume8
Issue number21
DOIs
StatePublished - Nov 1 2009
Externally publishedYes

Keywords

  • ABT-888
  • Immunohistochemistry
  • PARP
  • Phase 0 clinical trial
  • Solid tumors and lymphomas

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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