The Stupp protocol is the standard treatment of glioblastoma multiform (GBM) which prognosis
The non-dividing nature of normal brain cells provides an opportunity to enhance the
therapeutic ratio by combining radiation with inhibitors of replication-specific DNA repair
pathways such poly(ADP-ribose) polymerase (PARP) inhibitors, thus inducing more cytotoxic
effects of DNA-damage related to treatment modalities, including alkylating reagents like
Olaparib, a potent PARP inhibitor, overcomes apoptotic resistance and sensitizes GBM cells
for death receptor-mediated apoptosis induced by TRAIL (Tumor necrosis factor-Related
Apoptosis Inducing Ligand). Moreover, inhibition of PARP activity increases cellular
sensitivity to ionizing radiation: it was even suggested to be more pronounced in tumors than
in normal tissue.
Lastly, progress in technical imaging and intensity-modulated-radiotherapy (IMRT) techniques
provide new possibilities for sparing healthy tissues.
HGGs are the most common and most aggressive primary brain tumor. There is a real need to
improve care management of GBM patients. Attempts to achieve cure by increasing radiation
dose result in unacceptable neurotoxicity. As for radiosensitizers, they can exacerbate
normal tissue damage.
Since GBM represent a rapidly dividing cell population within the nonreplicating normal
brain, the therapeutic ratio may be enhanced by specific radiosensitization of proliferating
cells. Resistance to apoptosis is a paramount issue in the treatment of HGG. Targeting PARP
by the inhibitors like olaparib can reduce proliferation and lowers the apoptotic threshold
of HGG (effect showed in vivo and in vitro).
In this context, we propose a phase I-IIa trail to investigate the toxicity and efficacy of
olaparib and TMZ concomitantly with radiotherapy in first line treatment of unresectable high
Correlation between treatment response and tumor profiling will allow us to identify
biomarkers that can be useful in treatment improvement and/or present a prognostic value.
Then, the transfer of this approach will be evaluated in terms of compatibility with the
requirements of diagnostic.
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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