Pharmacology Core

PROJECT DESCRIPTION/ABSTRACT – PHARMACOLOGY CORE The Pharmacology Core will work closely with the project teams and the Therapy Evaluation Core to provide comprehensive pharmacology support for all proposed studies. The studies supported by the Pharmacology Core will address key pharmacologic issues and will inform crucial “go-no go” decisions in novel drug

development for GBM, including issues surrounding blood-brain barrier (BBB). Understanding the ability of drugs

to distribute across the BBB into tumor tissue and surrounding ‘normal’ brain infiltrated by GBM cells is critically important for the development of effective therapies, especially those treatments that could lead to long-term survival. The proposed Center projects are focused on developing combinatorial regimens using DNA damage

response (DDR) inhibitors targeting the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) signaling pathways (Project 1) or the p53/murine-double minute 2 (MDM2) pathway (Project 2). Efficacy of these combination strategies is dependent on adequate drug exposure at optimal times throughout the tumor volume,

including the infiltrative regions. Further, both projects will use a rigorous spatial evaluation of pharmacokinetic (PK) processes and resulting pharmacodynamic (PD) effects of these drugs within normal brain and throughout brain tumor tissues to design and implement the most efficacious combination regimens. The Pharmacology

Core is led by Dr. William Elmquist, who is a Professor of Pharmaceutics at the University of Minnesota and a world expert in the PK of drug distribution across the blood-brain barrier (BBB) into normal brain and brain tumors. His key co-investigators include Dr. Forest White from Massachusetts Institute of Technology and Dr.

Nathalie Agar from Harvard University. These three research groups have an extensive collaborative history, and many of the strategies planned have been rigorously validated through this close collaboration across the three laboratories. The specific functions of this Pharmacology Core can be divided into three specific Aims:

Specific Aim 1: Pharmacokinetic and CNS distribution analyses of novel therapeutic agents Specific Aim 2: Support the development of pharmacodynamic biomarkers Specific Aim 3: Support human Phase 0/1 clinical trial development