Abstract 3514: LT-00673, a highly potent PARP inhibitor, shows antitumor activity against tumor cells with DNA repair deficiencies

Abstract

Abstract Poly (ADP-ribose) polymerases (PARP) −1 and −2 are key nuclear enzymes that are activated by DNA damage and play a critical role in the base excision DNA repair (BER) pathway. Previous studies have indicated that inhibitors of PARP-1 and −2 could enhance the tumor cytotoxicity of DNA damaging agents by preventing cancer cells from repairing DNA damage. In addition, PARP inhibitors have been shown to selectively kill cancer cells that are deficient in BRCA-1 or BRCA-2 function. More recently, it was further suggested that other genetic deficiencies, such as PTEN gene mutation and malfunction of DNA mismatch repair, may also sensitize cells to cytotoxicity of PARP inhibitors. We have previously reported a novel PARP inhibitor, called LT-00673, that inhibits PARP-1 with IC50 of 0.58 nM. LT-00673 is also a potent inhibitor of PARP-2, but does not inhibit poly (ADP-ribose) glycohydrolase (PARG). In cell culture studies, LT-00673 potentiates chemotherapeutic agents such as temozolomide and SN-38, and displays potent single-agent cytotoxicity in BRCA-1 and BRCA-2 mutant cells. In xenograft tumor model studies, daily oral dosing of LT-00673 significantly enhances the antitumor effects of cytotoxic therapies in a dose-dependent manner. Furthermore, once daily oral dosing of LT-00673 at 0.33 mg/kg/day results in tumor regression in the MX-1 model (BRCA-1 deficient). In the current study, we further investigated the pharmacokinetic properties of LT-00673 in dogs and rats, and compared antitumor efficacies of different dosing schedules of LT-00673 using xenograft tumor models. We also demonstrated that several PTEN-deficient human cancer cell lines are highly sensitive to LT-00673 as a single agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3514.