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

Authors: Xu, R.; Shimizu, F.; Hovinga, K.; Beal, K.; Karimi, S.; Droms, L.; Peck, K. K.; Gutin, P.; Iorgulescu, J. B.; Kaley, T.; DeAngelis, L.; Pentsova, E.; Nolan, C.; Grommes, C.; Chan, T.; Bobrow, D.; Hormigo, A.; Cross, J. R.; Wu, N.; Takebe, N.; Panageas, K.; Ivy, P.; Supko, J. G.; Tabar, V.; Omuro, A.
Article Title: Molecular and clinical effects of notch inhibition in glioma patients: A phase 0/I trial
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. © 2016 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 22
Issue: 19
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2016-10-01
Start Page: 4786
End Page: 4796
Language: English
DOI: 10.1158/1078-0432.ccr-16-0048
PROVIDER: scopus
PMCID: PMC5050072
PUBMED: 27154916
Notes: Article -- Export Date: 2 November 2016 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Timothy Chan
    213 Chan
  2. Viviane S Tabar
    117 Tabar
  3. Philip H Gutin
    152 Gutin
  4. Antonio Marcilio Padula Omuro
    176 Omuro
  5. Kathryn Beal
    157 Beal
  6. Sasan Karimi
    97 Karimi
  7. Adilia Hormigo
    48 Hormigo
  8. Thomas Kaley
    82 Kaley
  9. Christian Grommes
    52 Grommes
  10. Katherine S Panageas
    325 Panageas
  11. Nian Wu
    30 Wu
  12. Kyung Peck
    78 Peck
  13. Craig Nolan
    42 Nolan
  14. Justin Robert Cross
    47 Cross
  15. Leif Asher Droms
    5 Droms
  16. Ran Xu
    5 Xu
  17. Dylan Nacht Bobrow
    3 Bobrow