Cell state‐directed therapy – epigenetic modulation of gene transcription demonstrated with a quantitative systems pharmacology model of temozolomide

Abstract

Cancer therapy continues to be plagued by modest therapeutic advances. This is particularly evident in glioblastoma multiforme (GBM) wherein treatment failures are attributed to intratumoral heterogeneity (ITH), a dynamic process of cell state transitions or plasticity. To address ITH, we introduce the concept of cell state-directed (CSD) therapy through a quantitative systems pharmacology model of temozolomide (TMZ), a cornerstone of GBM drug therapy. The model consisting of multiple modules incorporated an epigenetic-based gene transcription-translation module that enabled CSD therapy. Numerous model simulations were conducted to demonstrate the potential impact of CSD therapy on TMZ activity. The simulations included those based on global sensitivity analyses to identify fragile nodes -MDM2 and XIAP -in the network, and also how an epigenetic modifier (birabresib) could overcome a mechanism of TMZ resistance. The positive results of CSD therapy on TMZ activity supports continued efforts to develop CSD therapy as a new anticancer approach. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Cell state-directed (CSD) therapy is introduced as a new anticancer strategy to combat intratumoral heterogeneity and cell state transitions that are a root cause of treatment failures.

Network Analyses of Brain Tumor Patients’ Multiomic Data Reveals Pharmacological Opportunities to Alter Cell State Transitions

“…There remains a critical need to improve the treatment of GBM. Due to the high degree of heterogeneity and plasticity of GBM cells, controlling cell state transitions may be a viable treatment strategy, and previously referred to as cell state-directed (CSD) therapy [33]. There have been a few different classifications proposed to describe the cell states of GBM [12, 13, 52].…”

“…The combination of phosphoproteomics with RNAseq data provides not only a more robust network that connects gene regulatory networks and downstream signaling pathways but also possible protein targets amenable to pharmacological intervention. This network model could be a foundation to implement CSD therapy to either promote or prevent desired cell state transitions [33]. To that end, a Boolean network model derived from the combined PPIN was constructed and used to conduct in-silico protein knockout simulations that serve as proxies for pharmacological intervention.…”

“…Our lab has previously explored how epigenetics and cell state transitions may result in TMZ resistance in GBM, and how it may be possible to overcome this resistance via cell state-directed (CSD) therapy [32, 33]. In this work, we utilized a multi-step computational pipeline that incorporated multi-omics data from GBM patients to more broadly explore mechanisms for cell-state transitions and identify key genetic and epigenetic mediators.…”

Quantitative Systems Pharmacology: A Foundation To Establish Precision Medicine–Editorial

“…Not to discount the challenges of QSP model building and validation, there is a place for theoretically grounded model simulations that may forge new paths of inquiry. For example, epigenetic modulation within the guise of QSP modeling has been shown via simulations to be a means to combat drug resistance, at least theoretically (Saini and Gallo, 2021;Saini et al, 2023). Naturally, such predictions seek data confirmation to embrace the drug therapy strategy.…”