NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma
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Sanaz Yahyanejad1, Henry King2, Venus Sosa Iglesias1, Patrick V. Granton1,3, Lydie M.O. Barbeau1, Stefan J. van Hoof1, Arjan J. Groot1, Roger Habets1, Jos Prickaerts4, Anthony J. Chalmers5, Daniëlle B.P. Eekers6, Jan Theys1, Susan C. Short2, Frank Verhaegen1, Marc Vooijs1
1Department of Radiotherapy (MAASTRO)/GROW, School for Developmental Biology and Oncology, Maastricht University, Maastricht, The Netherlands
2Radiation Biology and Therapy Group, Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, England
3Department of Oncology, London Health Sciences Center, London, Ontario, Canada
4Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
5Translational Radiation Biology, Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, Scotland
6Department of Radiation Oncology, Maastro Clinic, Maastricht, The Netherlands
Marc Vooijs, email: firstname.lastname@example.org
Keywords: glioblastoma, RO4929097 NOTCH inhibitor, temozolomide, image guidance radiotherapy, glioma stem cells
Received: December 16, 2015 Accepted: April 10, 2016 Published: May 10, 2016
Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenograft models. Here we show using an image guided micro-CT and precision radiotherapy platform that a combination of the clinically approved NOTCH/γ-secretase inhibitor (GSI) RO4929097 with standard of care (TMZ + RT) reduces tumor growth and prolongs survival compared to dual combinations. We show that GSI in combination with RT and TMZ attenuates proliferation, decreases 3D spheroid growth and results into a marked reduction in clonogenic survival in primary and established glioma cell lines. We found that the glioma stem cell marker CD133, SOX2 and Nestin were reduced following combination treatments and NOTCH inhibitors albeit in a different manner. These findings indicate that NOTCH inhibition combined with standard of care treatment has an anti-glioma stem cell effect which provides an improved survival benefit for GBM and encourages further translational and clinical studies.
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