INVOLVEMENT OF LONG NON-CODING RNA MECHANISMS IN GLIOBLASTOMA

Despite aggressive therapy combining surgical resection, radiation and chemotherapy with Temozolomide (TMZ),
patients with glioblastoma (GBM) have a very poor prognosis, mainly due to tumour recurrence and resistance to
therapy. There is an urgent need to develop improved treatment strategies based on novel molecular targets.
Although some TMZ response markers such as the O6-methylguanine methyltransferase (MGMT) have been
identified, there is currently little knowledge on the molecular pathways that may help to overcome therapeutic
resistance. So far, transcriptional analysis upon TMZ treatment has mainly focused on mRNA studies using
classical adherent GBM cell lines that do not display typical genetic features and in vivo phenotypes of GBM.
Using RNA-Sequencing on GBM patient derived glioma cells treated with TMZ, we have uncovered a complex
transcriptional response to TMZ involving different classes of RNAs both coding and non-coding, in particular a
large number of long non-coding RNAs (lncRNAs). LncRNAs are thought to play an important role in cancer by
regulating transcriptional programs and interaction with epigenetic components. Using advanced systems
approaches, we identified 25 key lncRNAs involved in transcriptional regulatory circuits upon TMZ and/or correlated
with GBM patient prognosis. In this project we will decipher the functional role of 2 long non-coding RNAs
(lncRNAs) in GBM and chromatin dynamic induced by TMZ, and evaluate their clinical potential as therapeutic
targets in vivo.
The strength of this project relies on the innovative analysis of non-coding RNAs in GBM and on the use of patient
derived clinical models that reflect human GBM biology.The functional validation of new predictors and possible
targets to counteract chemoresistance is a priority clinical question and this project will pave the way for improved
therapies against this deadly cancer.