Dual molecular therapy targeting tumor cell heterogeneity improves therapeutic efficacy in glioblastoma

Area of Science:

• Oncology
• Pharmacology
• Genomics

Background:

• Glioblastoma exhibits intratumoral heterogeneity, with glioblastoma stem cells (GSCs) and differentiated glioblastoma cells (DGCs) contributing to treatment resistance.
• Targeting both GSCs and DGCs represents a promising strategy to overcome therapeutic challenges in glioblastoma.

Purpose of the Study:

• To explore combination therapy targeting both GSCs and DGCs in glioblastoma.
• To identify effective drug candidates through in silico screening and validate their efficacy in vitro.

Main Methods:

• In silico screening using antitumor efficacy data and gene expression profiles to identify candidate drugs.
• In vitro cell proliferation assays to determine IC50 values.
• Transcriptome and histological analyses to elucidate the molecular mechanisms and effects of combination therapy.

Main Results:

• Belinostat and Dasatinib were identified as effective agents against GSCs and DGCs, respectively.
• The combination of Belinostat and Dasatinib demonstrated synergistic effects in vitro.
• Combination therapy suppressed G2/M transition and the PI3K-Akt-mTOR pathway, leading to reduced proliferation and increased apoptosis.

Conclusions:

• In silico screening successfully identified potential drugs for targeting glioblastoma's heterogeneous cell populations.
• Dual targeting of GSCs and DGCs with Belinostat and Dasatinib offers a potential therapeutic approach to overcome glioblastoma's intratumoral heterogeneity and treatment resistance.