Research Project: Identification of novel therapeutic miRNA candidate for targeting the NOTCH signaling pathways in temozolomide resistant glioblastoma cells
Abstract
Description
The introduction of temozolomide (TMZ) as part of standard treatment for glioblastoma in addition to surgical resection and radiotherapy has proven to be a milestone, but in several cases, the patient prognosis remains poor. This can be due to the underlying drug resistance mechanisms which lead to therapeutic failure of TMZ in glioblastoma patients. The molecular mechanism of TMZ resistance remains to be fully understood. With the growing understanding of cancer stem cells in glioblastomas, developmental pathways like Hedgehog and Notch signaling have been implicated in drug resistance. Although few early reports suggesting the role of Notch signaling in chemo-resistance have started to emerge, the molecular mechanism of Notch signaling in TMZ resistance in glioblastoma remains to be fully explored. Our preliminary study confirmed the overexpression of activated Notch1 in chemo-resistant U87 glioblastoma cell line. Also, the inhibition of Notch1 using DAPT inhibitor enhanced the TMZ sensitivity in chemo-resistant cells. Therefore, in the present study, we hypothesize that gaining a better understanding of key molecular players, specifically, microRNAs (miRNA) associated with the Notch signaling pathway would prove pivotal in overcoming TMZ resistance in glioblastoma. For this purpose, firstly we will select miRNAs using bioinformatics target prediction tools. Later, we will investigate the expression pattern of selected miRNA in chemo-resistant and Notch1 knockout chemo-resistant U87 model in-vitro and in-vivo. This study could act as an adjunct in understanding the molecular mechanism of TMZ resistance in glioblastoma and aid in defining new targeted therapeutic strategies for chemo-resistance in glioblastoma.