Artikel
Monitoring the molecular consequences of Notch inhibition in glioblastoma during a Phase 1 trial
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Veröffentlicht: | 8. Juni 2016 |
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Gliederung
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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.