Prior Funding

"Transdifferentiation is the molecular underpinning of targeted therapy
resistance in gliomas"
Principal Investigator: Dr. Jihye Paik
Institution: Weill Medical College of Cornell University

Glioblastoma is the most common type of brain tumor and is still
incurable. The long-term goal of our study is to understand glioma
pathogenesis at a molecular level in order to develop effective therapies.
Scientists examining human glioblastomas have found many mutations
in a cell-surface receptor called epidermal growth factor receptor, or
EGFR. These mutations cause EGFR to be much more highly activated
than usual. As the name implies, EGFR has strong growth-promoting
functions and has been associated with several cancers. Unfortunately,
however, drugs targeting EGFR have failed to provide survival benefits to
glioblastoma patients. Our objective is to determine why these drugs are
ineffective and develop strategies to overcome their limitations.
We have begun investigating this issue using human and mouse glioma
cells that we know are dependent on EGFR signaling. When we reduced
EGFR expression in the cells, they underwent a change in cell type,
specifically a mesenchymal subtype transition. Mesenchymal cells are
relatively undifferentiated and can develop into a broad range of cell
types. In our EGFR-inhibited cells, we also noticed an increase in the
expression of a transcription factor called SLUG, which is known to
promote a mesenchymal phenotype in developing embryos. When we
tried forcing SLUG expression in primary glioma cells, we indeed
observed our cells transitioning to a mesenchymal state, resembling
tumors in relapsing patients.
Based on these findings, we hypothesize that the source of anti-EGFR
therapy resistance is the transition of glioma cells to a mesenchymal
state wherein they no longer depend on EGFR signaling. Therefore,
therapies should be developed that target both EGFR signaling and the
subsequent emergence of mesenchymal cancerous tissue.