We have a number of ongoing projects, briefly described below, related to drug development, drug interactions, drug resistance and drug transport in brain tumor models. Our research is supported by the NIH and the National Brain Tumor Society.
Project 1: Drug Resistance to Angiogenesis Inhibitors
We have come to understand the effects of angiogenesis inhibitors on the tumor vasculature and how vascular permeability may be altered to influence distribution or exposure to coadministered cytotoxic agents such as temozolomide. These drug interactions are pharmacodynamically-mediated at the level of the tumor. Recent efforts are investigating how brain tumors become resistant to angiogenesis inhibitors based on the use of in vivo models of resistance and genomic and proteomic measurements.
Project 2: Drug Development of Anticancer Drugs for Brain Tumor Chemotherapy
We have implemented a 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 will be further characterized for their mechanism of action in preclinical brain tumor models. The project is expanding its efforts to employ “omic”-based methods to the drug discovery and development process.
Project 3: Analysis of PK/PD Tumor Heterogeneity
There is an increasing appreciation that tumors are heterogeneous in terms of their genomic 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. This information could be critical to understand why drugs are effective or not and lead to new methods to optimize chemotherapy.
Project 4: The Role of Membrane Transporters on Drug Disposition
We are interested to understand how ABC transporters influence the PK properties of drug, and are particularly focused on the role of transporters at the BBB and tumor cell membrane. In both instances the transporters most often act as drug efflux pumps decreasing exposure to tumor cells. We use a combination of in vitro cell systems with expressed transporters and gene knockout mouse models to provide a complete PK assessment. These investigations are linked to primary CNS lymphoma [PCNSL] since a number of the agents currently used for PCNSL are substrates for different ABC transporters. We are also studying the PD characteristics of the drugs in preclinical models of PCNSL so that ultimately we can develop mechanistic PK/PD models that can be used to design improved chemotherapy.