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

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.