Poly (Adp-Ribose) Polymerase Inhibitor Lt-626 Sensitizes Lung And Pancreatic Cancers To Fractionated Radiation Therapy

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The development of stereotactic body radiation therapy (SBRT) has revolutionized radiation therapy for lung cancers and is an emerging treatment option for pancreatic cancers. However, there are many questions on how to optimize its use in chemoradiotherapy. The most relevant addition to radiotherapy regimens are inhibitors of DNA repair and DNA damage response pathways. One such class of agents are small-molecule inhibitors of poly (ADP-ribose) polymerase (PARP). PARP inhibitors target DNA base excision repair and radiosensitize cells through impaired DNA repair. In this study we examined the effects of the PARP inhibitor LT-626 (BioMarin) together with ionizing radiation in lung and pancreatic cancers, in vitro and in vivo. Clonogenic assays showed that lung cancer cells H1299 and H460 and pancreatic cancer cells Miapaca2 and PDA were sensitive to LT-626 (IC50 from 0.1-5.8 µM) and irradiation (IC50 from 2.2-5.9 Gy). Next, we found the combination of LT-626 and irradiation effective for inhibiting growth in lung and pancreatic cancer cells. Our study showed that both 1 and 10 µM concentrations of LT-626 were highly synergistic with 2, 4 and 6 Gy of irradiation in lung and pancreatic cell lines. Furthermore, in a fractionated radiation regimen study pretreatment with LT-626 followed by irradiation for three days significantly decreased cell survival as studied by clonogenic assay compared to LT-626 or radiation alone. Lung and pancreatic cancer cells treated with LT-626 and irradiation also exhibited DNA damage as evident by increased γH2AX and Rad51 foci formation. However, DNA damage caused by irradiation peaked by 2-4 h following treatment compared with LT-626 treated cells which exhibited maximum DNA damage around 24 h after treatment. Our in vitro study clearly demonstrated that PARP inhibition enhanced the efficacy of irradiation; we therefore decided to study the efficacy LT-626 and radiation therapy in vivo, using two lung xenograft (H1299 and H460) cancer models. After tumor implantation mice were treated with either drug alone (10mg/kg or 20 mg/kg) or radiation alone (2 Gy) or a combination of drug and radiation for five consecutive days after which they were followed until the end of the study. We found that combination of radiation plus LT-626 significantly decreased tumor burden in both H1299 and H460 xenograft models compared to drug alone or radiation alone group. Moreover, the median survival in combination treated animals more than doubled compared to vehicle treated group. Overall our in vitro and in vivo studies proved that PARP inhibitor LT-626 acts synergistically with fractionated irradiation in lung and pancreatic cancers. Citation Format: Kedar Hastak, Lisa McPherson, Yuqiao Shen, Renate Parry, James M. Ford. Poly (ADP-ribose) polymerase inhibitor LT-626 sensitizes lung and pancreatic cancers to fractionated radiation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5490. doi:10.1158/1538-7445.AM2014-5490