Alternative Targets

Research in the Stiles laboratory is focused on preventing the signaling of the transcription factor Olig2. Olig2 is expressed in brain progenitor cells are thought to give rise to PLGA. Transcription factors such as Olig2 bind to specific genes within the cell and stimulate or repress the expression of these genes. The Olig2 protein is expressed only within the brain and only within a limited number of cell types in the normal brain. During embryonic development, Olig2 is essential for proper formation of motor neurons and oligodendrocytes. However adult animals can survive for extended periods of time without Olig2. What makes Olig2 a particularly attractive target for drug development is that beyond simply marking PLGA cells, Olig2 is actually required for the malignant growth of “genetically relevant” murine models.

For technical reasons, transcription factors are generally poor targets for drug development. However we have identified a “surrogate target” for development of Olig2 antagonists. The Olig2 protein needs to be phosphorylated by a second set of proteins known as protein kinases in order for it to promote tumor cell growth. Protein kinases lend themselves readily to drug development. During the past year considerable progress has been made in identifying the protein kinases that phosphorylate Olig2. Currently, researchers in the Stiles laboratory are testing small molecule inhibitors of these protein kinases to determine if they can inhibit the growth of PLGA cells grown in culture.

Researchers in the laboratories of Loren Walensky, MD, PhD and Charles Stiles, PhD are focused on the creation of synthetic peptidomemetics of Olig2, using stapled peptide chemistry.  The goal of the project is to interfere with the functions of Olig2 binding to DNA directly.

Selected Publications

Separated at birth? The functional and molecular divergence of OLIG1 and OLIG2
Nat Rev Neurosci. 2012 Dec;13(12):819-31. PMID:23165259.