Immunohistochemical detection of poly(ADP-ribose) polymerase inhibition by ABT-888 in patients with refractory solid tumors and lymphomas
Volume 8, Issue 21
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November 1, 2009
Pages 2004 - 2009http://dx.doi.org/10.4161/cbt.8.21.9917
Authors: 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 and The National Cancer Institute Phase 0 Working Group View affiliations
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.