Abstract 8: Targeting DNA-damage response pathway with a novel nano-liposomal ATR inhibitor in solid tumors

Abstract

Abstract Introduction. Ataxia telangiectasia and Rad3-related (ATR) protein kinases have been identified as a key part of the DNA damage repair processes (DDRP) and cell cycle signaling. The DDRP is known to stimulate DNA repair, promote cell survival and, consequently, can diminish the therapeutic effect of existing DNA-damaging chemotherapy agents and ionizing radiation (IR) therapy. Therefore, there is a need for the development of potent and selective therapies to deliver ATR inhibitors for the treatment of cancer, as part of rational combination regimens with DNA damaging therapies. In this work, we develop and characterize a novel inhibitor of ATR kinase (BG129) and its nano-liposomal formulation (nLs-BG129). Methods. In vitro activity of novel ATR inhibitors (BG129) was tested in a broad panel of cancer cell lines as a monotherapy or in combination with DNA-damaging chemotherapeutics (carboplatin, gemcitabine, and SN-38). On-target effects of BG129 in vitro were evaluated by Western-Blot to demonstrate dose-dependent inhibition of pChk1 and pRPA2, and a corresponding increase in γH2AX. The ATR inhibitor was encapsulated into unilamellar liposomal vesicles formed from hydrogenated soy phosphatidylcholine (HSPC), cholesterol, and methoxy-poly(ethylene glycol)-1,2-distearoyl-sn-glyceryl (PEG2000-DSG) at a 3:2:0.15 molar ratio and loaded stably into liposomes employing a triethylammonium sucroseoctasulfategradient. Liposomes were characterized by size and drug loading efficiency. Pharmacokinetic (PK) properties of nLs-BG129 were evaluated in mice. The antitumor activity of nLs- BG129 in combination with nano-liposomal irinotecan (nal-IRI) was tested in vivo in ovarian and various lung cancer xenograft models. Results. BG129 synergized with SN-38, gemcitabine, and carboplatin in vitro in cell-based assays. On-target dose-dependent inhibition of pChk1 and pRPA2 and a corresponding increase in γH2AX were observed in cells, following treatment with BG129. Nano-liposomal BG129 showed dramatically improved pharmacokinetics (AUC = 2835 μg/ml*h), compared to either free BG129 or VE-822/M6620/Berzosertib (AUC = 18.18 μg/ml*h). nLs-BG129 also enhanced antitumor activity of nal-IRI in multiple ovarian and SCLC and NSCLC xenograft models, when given in combination and was well tolerated. Conclusions. Here we introduced a novel nano-liposomal formulation of an ATRi with good in vivo stability and prolonged clearance, with the ability to enhance the anti-tumor activity of DNA-damaging chemotherapeutics in vivo. The nano-liposomal formulation of ATRi can potentially sensitize tumor responses to DNA-damaging agents and improve their activity and tolerability in cancer patients when compared to unencapsulated and fast clearing ATR inhibitors, such as those currently in the clinic. Citation Format: Alexander Koshkaryev, Ozan Alkan, Bolin Geng, Lia Luus, Andreas Raue, Walid Kamoun, Suresh Tipparaju, Dmitri Kirpotin, Daryl Drummond. Targeting DNA-damage response pathway with a novel nano-liposomal ATR inhibitor in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 8.