Abstract 3305: WSD-0628, a novel brain penetrant ATM inhibitor, radiosensitizes GBM and melanoma patient derived xenografts

Le résumé fourni par la source

Abstract Glioblastoma (GBM) are inherently resistant to radiation therapy (RT), and development of radiosensitizers is one strategy to overcome this limitation. Repair of DNA double strand breaks induced by RT are mediated by the protein kinase Ataxia Telangiectasia mutated (ATM). In this study, the novel ATM inhibitor WSD-0628 was evaluated in combination with RT using GBM and melanoma models. In vitro evaluation of 10uM WSD-0628 binding to a panel of potential drug targets, including receptors, ion channels, enzymes, and transporters, indicated a satisfactory safety profile with low risk for off-target liability. WSD-0628 potently inhibits ATM-mediated phosphorylation of the DNA damage response protein KAP1 in MCF-7 cells at sub-nanomolar (nM) concentrations (IC50 0.42nM) in comparison to much less potent inhibition of the related kinases ATR (phosphorylation of CHK1, IC50 742nM) or DNA-PKcs (auto-phosphorylation of DNA-PK, IC50 169nM) in HT29 cells assessed by ELISA. In U251 GBM cells, 30 nM WSD-0628 potently inhibited RT-induced phospho-KAP1 and robustly reduced clonogenic survival by 5-fold when combined with 5 Gy irradiation (combination vs RT alone, p<0.01). Similar potent radiosensitizing effects were seen in a melanoma brain metastasis PDX line M12 (10nM WSD-0628+IR-5Gy 1% survival vs 5% survival with IR-5Gy alone. p<0.01), and the SV-40 transformed astrocyte line SVG-A (10nM WSD-0628 + IR-2.5Gy survival 0.2% vs 15% with IR-2.5Gy alone. p<0.01). Evaluation of the pharmacokinetic profile of WSD-0628 in mice 2h after a single 5 mg/kg oral dose reveals a high level of free drug availability in the brain (34nM) and in the CSF (50nM) with little to no Pgp/BCRP substrate liability. An initial in vivo dose finding study in orthotopic GBM43 PDX yielded significant benefit with WSD-0628 at either 5 or 10 mg/kg PO daily when combined with radiation (2Gy QD for 5 days); Median survival for sham RT (29d) or RT alone (34d) were significantly different from RT combinations with 5 mg/kg (54d) and 10 mg/kg (73d; p<0.01 for both dose levels), although the higher dose combination was poorly tolerated with body weight loss between 15-20% one week after RT completion. Dosing of WSD-0628 (7.5 mg/kg PO, QD) given just before and 24h after a single dose of RT (12.5Gy) in mice with orthotopic M12 was well tolerated and provided robust radiosensitizing effects with median survival for combination treatment of over 180d vs 17d for control and 49d with RT alone groups (combination vs RT alone, p=0.04). Collectively, these results suggest a promising role for WSD-0628 in combination with RT in GBM and melanoma metastatic to the brain. Citation Format: Ann Mladek Tuma, Wei Zhong, Lily Liu, Danielle M. Burgenske, Brett L. Carlson, Katrina K. Bakken, Zeng Hu, Margaret A. Connors, Jann N. Sarkaria. WSD-0628, a novel brain penetrant ATM inhibitor, radiosensitizes GBM and melanoma patient derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3305.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.