Soutenance de Thèse de Mme Marion SICOT

The November 16, 2023

Novel localized therapeutic strategies able to inhibit the O6-methylguanine-DNA-methyltransferase (MGMT) for the improvement of the post-resection glioblastoma standard of care

Patients with glioblastoma (GBM) are currently treated according to the Stupp protocol, which includes surgery followed by radiotherapy and concomitant chemotherapy with temozolomide (TMZ). One of the causes of treatment resistance is the expression of O6-methylguanine-DNA methyltransferase (MGMT). MGMT is part of the main DNA repair mechanisms, and this protein removes alkyl groups from DNA. However, the pharmacological action of TMZ, an alkylating agent, involves adding methyl groups to DNA to destroy tumor cells. MGMT inhibits the action of TMZ, posing a major problem as half of GBM patients overexpress MGMT. To improve patient care, two avenues of enhancement to the standard protocol have been explored: local delivery through hydrogel implants and MGMT inhibition. First, a hydrogel platform composed of lipid nanocapsules cross-linked with covalent bonds, was developed to allow the sustained release of active molecules. Ursolic acid was then selected for its ability to inhibit MGMT and formulated into nanoprecipitates to enhance its efficacy. This led to improved MGMT inhibition and sensitization of resistant cells to TMZ. Finally, these nanoprecipitates were incorporated into a thermosensitive hydrogel for local and sustained administration. These innovative approaches could potentially improve the prognosis and quality of life for GBM patients, representing a significant advancement in the fight against this aggressive brain tumor.

Directeur de Thèse: Dr. Guillaume BASTIAT