Comprehensive Preclinical Evaluation Of Ve-822, The First Atr-Targeted Drug Candidate: A Novel Approach To Transforming The Efficacy Of Dna Damaging Agents.

DNA damaging agents have been the cornerstone of cancer therapy for decades yet they provide only modest benefit for most patients. For example, standard of care for patients with non-small cell lung cancer (NSCLC) is dominated by the use of platinating drugs and ionizing radiation (IR), however outcome remains very poor with 5-year survival rates of VE-822 potently inhibits ATR in biochemical assays with Ki 90% of lines showed >3-fold shifts in IC50 for cisplatin in the presence of VE-822, with ~50% of lines showing >10-fold increases in cisplatin cytotoxicity. In contrast normal cells tolerate inhibition of ATR. In a panel of mouse xenograft models, derived from various primary human NSCLC tumor tissues, oral or IV administration of VE-822 strongly sensitized tumors to cisplatin treatment. In many cases, combinations including VE-822 led to tumor regression or extensive tumor growth delay. Inhibition of ATR activity and accumulation of DNA damage by VE-822 was observed coincident with efficacy. When administered alone or in combination with cisplatin VE-822 was well tolerated in mice at doses that block ATR activity. These data support the potential for ATR inhibitors to substantially increase the efficacy of standard-of-care agents in diseases such as NSCLC. Citation Format: Diane Boucher, Peter Charlton, Jean-Damien Charrier, Brinley Furey, Yong Gu, Amy Hall, Brian Hare, Howard Li, Sean Milton, Cheryl Murphy, Philip Reaper, Darin Takemoto, Taturo Udagawa, Yuxin Wang, Mark Wood, John Pollard. Comprehensive preclinical evaluation of VE-822, the first ATR-targeted drug candidate: a novel approach to transforming the efficacy of DNA damaging agents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-299. doi:10.1158/1538-7445.AM2013-LB-299