Research Projects

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. These studies support the development of mechanistic PK/PD models that we will scale from preclinical studies to virtual patients that can inform on which patients are likely to benefit from the drug and how to design early clinical trials.

Project 2: Analysis of PK/PD Tumor Heterogeneity
There is an increasing appreciation that tumors are heterogeneous in terms of their genomic and proteomic characteristics that will likely impact drug efficacy. We are developing methods to determine the regional variability in the PK/PD of anticancer drugs in brain tumors. One approach we have developed is referred to as cell-type specific PK/PD models that are based on linking PK and PD intracellularly at the molecular level. Since these models can contrast drug action and toxicity in different cell types they offer a means to account for tumor heterogeneity and provide novel ways to assess and design drug therapy.

Project 3: Disposition of Oncometabolites and Their Inhibitors
Many brain tumors possess a mutant isocitrate dehydrogenase [mIDH1] enzyme that produces an oncometabolite, D-2-hydroxyglutarate [D2HG]. We are evaluating the CNS disposition of mIDH1 inhibitors and D-2HG to determine optimal means to suppress 2HG and to combine these enzyme inhibitors with other drugs.

Project 4: Development of PK/PD Models for Epigenetic Modulators

Epigenetic mechanisms are an important determinant of gene and protein expression that has generated numerous efforts to design and develop drugs known under the umbrella of epigenetic modulators. We are interested in drugs able to inhibit histone demethylase enzymes in brain tumors.