Abstract 1795: Potent anti-tumor activity of talazoparib (BMN673) in combination with radiation for squamous cell carcinoma of the head and neck
Authors: Deborah JL Wong, David D. Shin, Josephine Ratikan, Meenal Chalukya, Kanthinh Manivong, Leonard Post, Dörthe Schaue, Richard S. Finn, Yuqiao (Jerry) Shen, William McBride, Dennis J. Slamon
Journal: Cancer Research (2015)

Abstract Background: Squamous cell carcinoma of the head and neck (SCCHN) is a radiation-sensitive disease. Standard frontline treatment of locally advanced SCCHN entails concurrent chemotherapy with radiation. Treatment of relapsed or metastatic SCCHN often utilizes re-irradiation to the primary tumor for local control. However, there is no standard systemic treatment for relapsed or metastatic SCCHN in combination with radiation. Many SCCHN tumors display alterations in expression of DNA repair genes. To this end, we evaluated the effect of talazoparib (BMN-673), a potent poly-ADP ribose polymerase (PARP) inhibitor, alone or in combination with radiation, in vitro and in vivo. Methods: The 50% inhibitory concentration (IC50) of talazoparib was determined in 30 SCCHN cell lines in vitro. Using clonogenic assays, the effects of 0, 10 or 100nM talazoparib, alone or in combination with a single fraction of 4Gray radiation were determined in four cell lines (two sensitive and two resistant to talazoparib). Effects on DNA damage of talazoparib, alone or in combination with radiation were also determined by flow cytometric analysis of Gamma-H2A.X. Finally, the FaDu head and neck cells were implanted onto female J/nude. After tumors were established, mice were treated with talazoparib for 5 days and a total of 20 Gray radiation, alone or in combination, and effects on body weight and tumor size were determined. Results: Among 30 SCCHN cell lines treated with talazoparib alone, 18 displayed sensitivity with 50% inhibitory concentration (IC50) of 1μM or less. In clonogenic assays, addition of radiation to BMN673 in two sensitive (UMSCC-6 and UMSCC-38) and two resistant (UMSCC-5 and UMSCC-12) cell lines resulted in synergistic cytotoxicity at doses ranging from 0-100nM BMN673. Increased gamma-H2A.X was seen when cell lines were treated with talazoparib, radiation, or the combination, compared to controls. Combining radiation with talazoparib resulted in a transient decrease in body weight in J/nude mice, but resulted in statistically significant and prolonged decrease in tumor volume. These anti-tumor effects were sustained out to 60 days post inoculation. Conclusions: The PARP inhibitor talazoparib with radiation synergistically inhibited tumor growth in vitro and in vivo in SCCHN cell lines. Further evaluation of this combination is underway. Citation Format: Deborah JL Wong, David D. Shin, Josephine Ratikan, Meenal Chalukya, Kanthinh Manivong, Leonard Post, Dörthe Schaue, Richard S. Finn, Yuqiao (Jerry) Shen, William McBride, Dennis J. Slamon. Potent anti-tumor activity of talazoparib (BMN673) in combination with radiation for squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1795. doi:10.1158/1538-7445.AM2015-1795