Screen of Glioblastoma Cancer Stem Cells with a Kinase Inhibitor Library
Glioblastoma Multiforme (GBM) is the most common and most aggressive form of brain
cancer in adults. Despite aggressive treatment modalities, median survival post
diagnosis has changed little since the 1980s and remains stagnant at 12-14 months. There
are a host of novel, targeted therapies being developed such as immunotherapy but up
until now, none of them has been able to extend ... read moreprogression-free survival in any
significant way. Because of this, research into the underlying mechanisms that control
cell proliferation and tumor invasion is critical to the development of more targeted
therapies. GBM is a prime example of the cancer stem cell theory in which a subset of
tumor cells with stem-like properties is responsible for the maintenance and recurrence
of tumors. These GBM stem cells (GSCs) are resistant to chemo- and radiotherapy making
their eradication the largest obstacle to treatment. We obtained a commercially
available kinase inhibitor (KI) library and used it to screen three of our GSC lines.
After incubating the cells with KIs for 6-8 days, we performed the PrestoBlue cell
viability assay to determine which compounds were growth inhibitory. Our results show
that inhibition of the kinases in the RTK/Ras/PI3K signaling pathway, commonly altered
in GBM, leads to significant suppression of GSC proliferation. Additionally, protein
kinase C (PKC) inhibitors were among the most effective compounds in the entire library.
We performed Western Blot analysis of the downstream targets of PKC in order to further
understand this result. We show that inhibition of PKC suppressed phosphorylation of
Ribosomal Protein S6 but had no effect on the activation of extracellular-signal related
kinases (ERK1/2) or Nuclear Factor Kappa-Light-Chain-Enhancer of B Cells (NF-κB)
Thesis (M.S.)--Tufts University, 2018.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisor: Brent Cochran.
Keyword: Cellular biology.read less