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Published on: February 8, 2018
Immunohistochemical detection of poly(ADP-ribose) polymerase inhibition by ABT-888 in patients with refractory solid
Sherry X Yang1, Shivaani Kummar, Seth M Steinberg
1Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA. yangxia@mail.nih.gov
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.
Insights
The poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 effectively targets tumors by reducing poly (ADP-ribose) (PAR) levels. This study confirms ABT-888
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Targeting the poly (ADP-ribose) polymerase (PARP) pathway is a key strategy in cancer therapy.
- PARP inhibitors are under active investigation in pre-clinical and clinical settings.
- Understanding drug efficacy at the molecular level is crucial for optimizing cancer treatment.
Purpose of the Study:
- To evaluate if the PARP inhibitor ABT-888 reaches and affects its target in human tumors.
- To quantify the impact of ABT-888 on poly (ADP-ribose) (PAR) and PARP-1 expression.
- To assess target engagement using immunohistochemistry in a Phase 0 clinical trial.
Main Methods:
- Quantitative immunohistochemistry was used to analyze tumor biopsies.
- Expression levels of PAR and full-length PARP-1 were measured.
- Samples were collected at baseline and at various time points after ABT-888 administration (25 or 50 mg).
Main Results:
- A significant reduction in PAR levels was observed post-ABT-888 administration (p = 0.03).
- PARP-1 expression increased in most tumors analyzed.
- The ratio of PAR to PARP-1 decreased significantly, indicating target engagement (p = 0.03).
Conclusions:
- ABT-888 successfully engages its therapeutic target in human tumors by reducing PAR levels.
- Significant variability in baseline tumor PAR levels was noted among patients.
- Future studies should investigate the correlation between baseline PAR levels and treatment response.
