Cell state-directed therapy - epigenetic modulation of gene transcription demonstrated with a quantitative systems...

Area of Science:

• Oncology
• Systems Pharmacology
• Computational Biology

Background:

• Cancer therapy faces challenges due to modest advances, especially in glioblastoma multiforme (GBM).
• Intratumoral heterogeneity (ITH), characterized by cell plasticity, is a key factor in GBM treatment failures.
• Current therapies often struggle to address the dynamic nature of cancer cell populations.

Purpose of the Study:

• To introduce and evaluate cell state-directed (CSD) therapy as a strategy to overcome ITH in GBM.
• To develop a quantitative systems pharmacology (QSP) model to simulate CSD therapy's impact on temozolomide (TMZ) efficacy.
• To identify potential therapeutic targets and combination strategies for enhanced GBM treatment.

Main Methods:

• Development of a QSP model incorporating an epigenetic-based gene transcription-translation module.
• Simulation of numerous scenarios to assess CSD therapy's effect on TMZ activity.
• Global sensitivity analyses to identify critical network nodes (MDM2, XIAP) and evaluate epigenetic modifiers (birabresib) in overcoming resistance.

Main Results:

• The QSP model demonstrated the potential of CSD therapy to modulate cell states and enhance TMZ activity.
• Sensitivity analyses identified MDM2 and XIAP as fragile nodes within the GBM network.
• Simulations showed that combining TMZ with an epigenetic modifier like birabresib could overcome specific resistance mechanisms.

Conclusions:

• CSD therapy presents a promising new approach to combat ITH in GBM.
• The developed QSP model provides a framework for designing and optimizing CSD strategies.
• Further development of CSD therapy holds potential for improving outcomes in GBM and other cancers characterized by heterogeneity.