gms | German Medical Science

67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

12. - 15. Juni 2016, Frankfurt am Main

Monitoring the molecular consequences of Notch inhibition in glioblastoma during a Phase 1 trial

Meeting Abstract

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  • Ran Xu - Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY; Klinik für Neurochirurgie, Charité-Universitätsmedizin Berlin, Berlin, Germany
  • Fumiko Shimizu - Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY
  • Philip Gutin - Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY
  • Viviane Tabar - Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY
  • Antonio Omuro - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY

Deutsche Gesellschaft für Neurochirurgie. 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS). Frankfurt am Main, 12.-15.06.2016. Düsseldorf: German Medical Science GMS Publishing House; 2016. DocMI.10.08

doi: 10.3205/16dgnc289, urn:nbn:de:0183-16dgnc2892

Veröffentlicht: 8. Juni 2016

© 2016 Xu et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Objective: Malignant gliomas (MG) are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO2929097 has emerged as a potential therapeutic option based on modulation of the cancer stem cell population (CSC) and a presumed anti-angiogenic role. This proof-of-concept trial was designed to determine the maximum tolerated dose, toxicities and pharmacokinetics as well as to evaluate tumor and brain drug penetration and effects of CSCs in tumor tissue.

Method: In this dose escalation phase I trial, 21 patients with newly-diagnosed MG received RO4929097 combined with temozolomide (TMZ) and radiotherapy (RT), followed by toxicity and pharmacokinetic studies. Additional exploratory studies included the evaluation of tumor and brain drug penetration, neuro-imaging parameters and effects on the Notch pathway and CSCs in tumor tissue sampled from areas with and without blood-brain barrier disruption. Recurrent tumors were also sampled while on treatment.

Results: Treatment was well tolerated and no dose-limiting toxicities were observed. Immunohistochemistry of treated tumors showed a significant decrease in proliferation and in the expression of the cleaved notch receptor (NICD) by tumor cells and blood vessels. Organotypic explant cultures of study patients revealed a decrease in proliferation, viability, and CD133+ CSC population with treatment. Perfusion MRI demonstrated a significant decrease in relative plasma volume after drug exposure. Gene expression data in recurrent tumors suggested low Notch signaling activity and an increase in VEGF-dependent angiogenic factors.

Conclusions: The combination of RO4929097 with TMZ and RT in newly-diagnosed malignant glioma is safe and well tolerated; the drug has variable blood brain barrier penetration with some evidence of target modulation, including inhibition of the Notch pathway and CSC population, as well as alterations in angiogenesis signaling pathway.