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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

Sherry X. Yang

National Clinic Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bldg 37.Rm 1048, 37 Convent Drive, Bethesda MD 20892

Shivaani Kummar

Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

Seth M. Steinberg

National Institutes of Heath, Bethesda, Maryland

Anthony J. Murgo

Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

Martin Gutierrez

Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

Larry Rubinstein

Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

Dat Nguyen

Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

Gurmeet Kaur

Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

Alice P. Chen

Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

Vincent L Giranda

Cancer Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL

Joseph E. Tomaszewski

Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

James H. Doroshow

Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bldg. 31/Rm. 3A44, 31 Center Dr., Bethesda, MD 20892

The National Cancer Institute Phase 0 Working Group

National Cancer Institute, National Institutes of Health; Bethesda, MD, USA

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.

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