2. Academic Validation
  3. Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits Potent Efficacy as Monotherapy for Primary Central Nervous System Lymphoma

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

  • Target Oncol. 2023 Nov;18(6):941-952. doi: 10.1007/s11523-023-01006-z.
Ning Wang 1 2,  Zhenxian Mo 3 4,  Lu Pan 1 2,  Minhua Zhou 3,  Xiaolan Ye 3,  Xinjian Liu 3,  Xiong Cai 3 5,  Changgeng Qian 3 5,  Feili Chen 1,  Yan Xiong 3,  Fushun Fan 6 7,  Wenyu Li 8 9
Affiliations

Affiliations

  • 1 Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangdong Academy of Medical Sciences, No. 123 Huifu West Road, Guangzhou, 510080, Guangdong, China.
  • 2 School of Medicine, South China University of Technology, Guangzhou, China.
  • 3 Guangzhou BeBetter Med Inc., No. 25 Yayingshi Road, Guangzhou, 510660, Guangdong, China.
  • 4 College of Life Science and Technology, Jinan University, 601 Huangpu Avenue West, Guangzhou, China.
  • 5 Curis, Inc., Lexington, MA, USA.
  • 6 College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, China. [email protected].
  • 7 Guangzhou BeBetter Med Inc., No. 25 Yayingshi Road, Guangzhou, 510660, Guangdong, China. [email protected].
  • 8 Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangdong Academy of Medical Sciences, No. 123 Huifu West Road, Guangzhou, 510080, Guangdong, China. [email protected].
  • 9 School of Medicine, South China University of Technology, Guangzhou, China. [email protected].
PMID: 37855991 DOI: 10.1007/s11523-023-01006-z
Abstract

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.

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