Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits Potent Efficacy as Monotherapy for Primary Central Nervous System Lymphoma

• Published in: Targeted oncology Vol. 18; no. 6; pp. 941 - 952
• Main Authors: Wang, Ning, Mo, Zhenxian, Pan, Lu, Zhou, Minhua, Ye, Xiaolan, Liu, Xinjian, Cai, Xiong, Qian, Changgeng, Chen, Feili, Xiong, Yan, Fan, Fushun, Li, Wenyu
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.11.2023; Springer Nature B.V
• Subjects: Biomedicine; Ferroptosis; Hematology; Lymphoma; Medicine; Medicine & Public Health; Nervous system; Oncology; Original Research Article
• ISSN: 1776-2596; 1776-260X
• DOI: 10.1007/s11523-023-01006-z

Background The efficacy of systemic treatment for primary central nervous system lymphoma (PCNSL) is limited because of the blood–brain barrier (BBB) and the ineffectiveness of chemotherapy. The dual PI3K/HDAC inhibitor BEBT-908 has exhibited favorable in vivo distribution and activity in various cancers. Objectives The aims of this study were to assess the efficacy of BEBT-908 in brain orthotopic mouse models of hematological malignancies, to investigate its pharmacologic properties, and to elucidate the underlying mechanism of action. Methods We evaluated the anticancer activity of BEBT-908 in various hematological malignancies through cell viability assays. The impact of BEBT-908 on c-Myc expression and ferroptosis signaling pathways was assessed using Western blotting, qPCR, ROS detection, GSH/GSSG detection, and IHC. Pharmacokinetic and pharmacodynamic profiles were assessed through LC–MS/MS and Western blotting. The effects of BEBT-908 in vivo were examined using xenografts and brain orthotopic mouse models. Results Our findings demonstrate that BEBT-908 exhibits promising anti-tumor activity in vitro and in vivo across multiple subtypes of hematological malignancies. Furthermore, BEBT-908 exhibits excellent BBB penetration and inhibits tumor growth in a brain orthotopic lymphoma model with prolonged survival of host mice. Mechanistically, BEBT-908 downregulated c-Myc expression, which contributed to ferroptosis, ultimately leading to tumor shrinkage. Conclusion Our study provides robust evidence for the dual PI3K/HDAC inhibitor BEBT-908 as an effective anti-cancer agent for PCNSL.