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 a platform to scale-up QSP models to patients. We believe the latter process can achieve precision medicine.
We have a number of ongoing projects, briefly described below.
Project 1: Drug Development of Anticancer Drugs for Brain Tumor Chemotherapy
We have implemented a systems-based PK/PD-driven drug development strategy to identify the most active drug in brain tumor models. This approach utilizes in vitro assays such as metabolic stability, blood-brain barrier [BBB] permeability and cytotoxicity to screen compounds that may be further characterized for their mechanism of action in preclinical brain tumor models. QSP models developed for the leading candidate drugs may be scaled to yield virtual patient simulations that can predict responders and non-responders and corresponding classification signatures. The individually tailored models provide a true precision medicine tool and pharmacologically-based means to design early clinical trials.
Project 2: Epigenetic Modulation of Drug Therapy
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. Post-translational modifications (PTM) of histones is intimately involved in epigenetic modulation and offers drug targets that can determine gene transcription and cell states. In addition, low-grade brain tumors often possess the mutant IDH1 enzyme that yields an oncometabolite (D2HG) that produces a methylator phenotype. Therefore, through modulation of enzyme targets related to PTM we propose drug therapy may be improved.
Project 3: Drug Therapy and Intratumoral Heterogeneity (ITH)
There is an increasing appreciation that brain tumors are 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 types, for example, glioma stem cells and glioma cells may respond differently to drugs due to differences in protein networks. We are interested to develop cell-type specific QSP models to account for ITH, and provide new drug targets and strategies to improve drug therapy.