Interdisciplinary Initiatives Program Round 10 - 2020
Michael Lin, Neurobiology and Bioengineering
Michelle Monje-Deisseroth, Neurology & Neurological Sciences
Many cancers are caused by unchecked activity of specific enzymes called kinases, whose activity sends signals inside cells to instruct them to grow and divide. Drugs that inhibit kinases are thus effective in treating a variety of cancers. However, kinase inhibitors have been developed primarily for cancers outside the brain, and the blood-brain barrier blocks access of most kinase inhibitors to the brain. Testing kinase inhibitors for effectiveness in brain cancers requires slow, expensive observations of their long-term effects on tumor growth in mice.
We propose a novel method for visualizing the effects of kinase inhibitors on their direct targets – kinase activity – within brain tumors in living mice, and to do so rapidly and noninvasively. We have engineered a protein that senses activity of a specific kinase and induces expression of any introduced gene only when the kinase is inhibited. We have also engineered a light-producing protein that is 55-fold brighter in the brain than previous ones, allowing us to visualize the brain anatomy of mice completely non-invasively. We propose to now integrate these components into a simple system for real-time, non-invasive imaging of kinase inhibition in brain tumors, which we call Drug Activity Reporter in Target Tissues (DARTT). Specifically, we will develop DARTT systems for the kinases ERK and mTOR to test the ability of various drugs to block the activity of these kinases in the brain. We will validate this system in diffuse intrinsic pontine glioma and pediatric cortical glioblastoma, cancers driven by ERK and mTOR activity, respectively. If successful, these experiments will establish a rapid and sensitive system for screening drug candidates for kinase inhibition in the brain, currently a major bottleneck in the development of better drugs for brain tumors.