Molecular and clinical effects of notch inhibition in glioma patients: A phase 0/I trial

Ran Xu, Fumiko Shimizu, Koos Hovinga, Kathryn Beal, Sasan Karimi, Leif Droms, Kyung K. Peck, Philip Gutin, J. Bryan Iorgulescu, Thomas Kaley, Lisa DeAngelis, Elena Pentsova, Craig Nolan, Christian Grommes, Timothy Chan, Dylan Bobrow, Adilia Hormigo, Justin R. Cross, Nian Wu, Naoko TakebeKatherine Panageas, Percy Ivy, Jeffrey G. Supko, Viviane Tabar, Antonio Omuro

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

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 ofRO4929097 totemozolomide and radiotherapy waswell 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.

Original languageEnglish (US)
Pages (from-to)4786-4796
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number19
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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