Details

Autor(en) / Beteiligte

• Roth, Patrick
• Papachristodoulou, Alex
• Signorell, Rea Deborah
• Werner, Beat
• Brambilla, Davide
• Grandjean, Joanes
• Rudin, Markus
• Martin, Ernst
• Leroux, Jean-Christophe
• Weller, Michael

Titel

DRES-14. OVERCOMING TEMOZOLOMIDE RESISTANCE IN EXPERIMENTAL GLIOMAS: MRI-GUIDED FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING FACILITATES THE LOCAL DELIVERY OF LIPOSOME ENCAPSULATED MGMT INHIBITORS

Ist Teil von

• Neuro-oncology (Charlottesville, Va.), 2017-11, Vol.19 (suppl_6), p.vi66-vi67

Ort / Verlag

US: Oxford University Press

Erscheinungsjahr

2017

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• The standard of care for patients with newly diagnosed glioblastoma comprises surgical resection followed by radiation therapy and chemotherapy with the alkylating agent, temozolomide (TMZ). Still, the median overall survival of glioblastoma patients is only approximately 16 months in clinical trial populations. Importantly, the survival benefit derived from the addition of TMZ is almost exclusively restricted to the rather small subgroup of patients with tumors harboring a methylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) gene promoter. The clinical development of drugs that inhibit MGMT in order to sensitize tumors to TMZ was largely unsuccessful because of systemic toxicity. We applied magnetic resonance image-guided focused ultrasound (MRIgFUS) to transiently open the blood brain barrier (BBB) in mice bearing MGMT-expressing experimental gliomas. We generated a novel MGMT inhibitor that was encapsulated in liposomes and resulted in a potent down-regulation of MGMT levels in glioma cells in vitro. The systemic administration of this liposomal MGMT inhibitor in combination with MRIgFUS strongly reduced MGMT levels in orthotopically growing gliomas. Transient opening of the BBB by MRIgFUS and subsequent treatment with the MGMT inhibitor and TMZ reduced the growth of experimental gliomas as assessed by MRI and conferred a significant survival benefit without signs of systemic toxicity. Our dataset demonstrates that MRIgFUS allows for transient and circumscribed BBB opening in the tumor region which can be used for targeted MGMT downregulation. Overcoming MGMT-mediated alkylator resistance sensitizes gliomas in vivo to TMZ, ultimately resulting in a survival benefit. Based on these data, a clinical assessment of this approach in human patients is warranted.