Research: Quantitative Systems Pharmacology (QSP) of Brain Tumor Drug Therapy
Our lab is focused on the experimental therapeutics of anticancer drugs used in brain tumors. We incorporate experimental and computational approaches to advance drug development and address unique biological and pharmacological challenges of brain tumor drug therapy. The net result of these efforts will hopefully improve drug therapy and lead to new chemotherapeutic strategies that enhance the translational foundation and integration of preclinical and clinical research.
Our computational paradigm relies on pharmacokinetic [PK], pharmacodynamic [PD] and quantitative systems pharmacology (QSP) approaches that provide a mechanistic underpinning of drug action. We are interested to depict cell-type specific phenomenon and models that can achieve precision therapeutics.
We have a number of ongoing projects, briefly described below.
Project 1: Single-Cell Pharmacodynamic Models that Drive Precision Therapeutics
We are calibrating PanCancer pharmacodynamic models to brain tumor patients and drugs, such as temozolomide. We seek to focus on drug non-responders and reformulate more effective drug regimens using their genomic data. The model predictions can be tested in preclinical models to establish the strategy.
Project 2: Epigenetic Modulation of Drug Resistance
The epigenetic landscape of brain tumors is a dynamic process that can be affected by a number of variables, and may likely have an important role in drug therapy and the evolution of drug resistance. Post-translational modifications (PTM) of histones are intimately involved in epigenetic modulation and offers drug targets that can determine gene transcription and cell states. Currently, we are focused on low-grade brain tumors that possess the mutant IDH1 enzyme that produces the oncometabolite (D2HG). D2HG produces a methylator phenotype and through its modulation we may alter cell state and susceptibility to drug resistance. The QSP models will integrate cell state and mechanistic data.
Project 3: Drug Therapy and Intratumoral Heterogeneity
There is an increasing appreciation that each patient’s brain tumor is highly heterogeneous, due to different cell types and physiological characteristics, which likely impact drug efficacy. Not only are there regional variations in brain tumor blood flow, oxygenation and blood-brain barrier permeability, but different cell states based on single-cell RNAseq analyses. Each glioma cell state may respond differently to drugs due to differences in the associated protein networks. We are interested to develop cell state mechanistic QSP models that provide new drug targets and strategies to improve drug therapy.