Abstract 5088: Exploring ATM deficiency as a potential therapeutic target for the PARP inhibitor olaparib in head and neck squamous cell carcinoma
Authors: Senra Joana M. , Donald Emma L. , Williams Victoria S. , Wombwell Helen , Hall Gillian , Harbron Chris G. , Telfer Brian A. , Morten John , Womack Chris , West Catharine M. , Hodgson Darren , O'Connor Mark J. , Wedge Steve R. , Stratford Ian J. 
Published: June 2012

Abstract
Background: Ataxia telangiectasia mutated (ATM) gene, localized in chromosome 11q22-23 is a key player in the signaling response to double strand breaks (DSBs). Impaired DSB repair due to ATM deficiency in tumor cells may lead to a wider application of the ‘‘synthetic lethality’’ approach seen with PARP inhibitors in BRCA-deficient tumors. Targeting DNA repair mechanisms with specific small molecule inhibitors will in principle sensitize tumor cells to DNA-damaging agents such as radiation. Radiation therapy remains the most common treatment of choice for head and neck cancers; however, there is still a large scope for improvement. Loss of distal 11q chromosome and subsequent ATM deficiency has been reported in primary head and neck tumors. Therefore, there are two aims to this work. First, we will establish the potential of targeting this cellular deficiency with the potent poly (ADP-ribose) polymerase (PARP) inhibitor olaparib; second, we will determine the prognostic significance of ATM deficiency in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy.
Methods: A panel of 10 HNSCC cell lines was screened for sensitivity to radiation in combination with olaparib by clonogenic survival assay in normoxic and anoxic conditions. The effect of olaparib as a single agent was also assessed in a PE/CA PJ34 (ATM deficient) xenograft model. A panel of 155 HNSCC biopsies taken prior to treatment with radiotherapy and where 5 year outcome data was available were used for ATM expression analysis by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH).
Results: Olaparib enhanced the effect of ionizing radiation (IR) in all HNSCC cell lines. In vitro, the increase in sensitivity to 2Gy after olaparib treatment ranged between 1.5- and 8.4-fold in normoxia and between 1.2- and 3.9-fold in anoxia. In vivo, administration of olaparib (50mg/kg p.o) as a single agent in PE/CA PJ34 xenografts daily for 5 days caused a substantial increase in tumor growth delay compared to vehicle alone. The IHC and FISH studies of the 155 HNSCC biopsies showed a variable level of ATM deficiency and the prognostic significance (if any) of these observations are being established.
Conclusion: We demonstrate that olaparib is a promising candidate as a single agent in tumors with ATM deficiency, and given the radiosensitizing effects in vitro and in vivo it warrants consideration for combining with radiation for the treatment of HNSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5088. doi:10.1158/1538-7445.AM2011-5088