Molecular and Clinical Effects of Notch Inhibition in Glioma Patients: A Phase 0/I Trial
| Autor: | Naoko Takebe, Ran Xu, Jeffrey G. Supko, J. Bryan Iorgulescu, Fumiko Shimizu, Christian Grommes, Timothy A. Chan, Sasan Karimi, Philip H. Gutin, Elena Pentsova, Craig Nolan, Nian Wu, Leif A. Droms, Lisa M. DeAngelis, Kyung K. Peck, Antonio Omuro, Dylan Bobrow, Justin R. Cross, Katherine S. Panageas, Adilia Hormigo, S. Percy Ivy, Kathryn Beal, Viviane Tabar, Thomas Kaley, Koos E. Hovinga |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research Pathology medicine.medical_specialty Maximum Tolerated Dose Angiogenesis Population Notch signaling pathway Biology Article Neovascularization 03 medical and health sciences 0302 clinical medicine Glioma medicine Humans education Aged education.field_of_study Temozolomide Neovascularization Pathologic Receptors Notch Brain Neoplasms Chemoradiotherapy Benzazepines Middle Aged medicine.disease 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Neoplastic Stem Cells Immunohistochemistry Female medicine.symptom Neoplasm Recurrence Local Anaplastic astrocytoma medicine.drug |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 22(19) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: High-grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO4929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed antiangiogenic role. Experimental Design: In this phase 0/I trial, 21 patients with newly diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the MTD, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuroimaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood–brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment. Results: Treatment was well tolerated and no dose-limiting toxicities were observed. IHC of treated tumors showed a significant decrease in proliferation and in the expression of the Notch intracellular domain (NICD) by tumor cells and blood vessels. Patient-specific organotypic tumor explants cultures revealed a specific decrease in the CD133+ CIS population upon 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, the upregulation of key mesenchymal genes, and an increase in VEGF-dependent angiogenic factors. Conclusions: The addition of RO4929097 to temozolomide and radiotherapy was well tolerated; the drug has a variable blood–brain barrier penetration. Evidence of target modulation was observed, but recurrence occurred, associated with alterations in angiogenesis signaling pathways. Clin Cancer Res; 22(19); 4786–96. ©2016 AACR. |
| Databáze: | OpenAIRE |
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