TY - JOUR
T1 - Screening of predicted synergistic multi-target therapies in glioblastoma identifies new treatment strategies
AU - Houweling, Megan
AU - Giczewska, Anna
AU - Abdul, Kulsoom
AU - Nieuwenhuis, Ninke
AU - Küçükosmanoglu, Asli
AU - Pastuszak, Krzysztof
AU - Buijsman, Rogier C.
AU - Wesseling, Pieter
AU - Wedekind, Laurine
AU - Noske, David
AU - Supernat, Anna
AU - Bailey, David
AU - Watts, Colin
AU - Wurdinger, Thomas
AU - Westerman, Bart A.
N1 - Funding Information: This project was supported by the Dutch Cancer Society grant KWF-4874, KWF-11026, and KWF-11038, Maurits en Anna de Kock foundation 2018-5, Brain Tumour Charity Grant 488097, and the Health~Holland AI Impact grant. Publisher Copyright: © The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - Background. IDH-wildtype glioblastoma (GBM) is a highly malignant primary brain tumor with a median survival of 15 months after standard of care, which highlights the need for improved therapy. Personalized combination therapy has shown to be successful in many other tumor types and could be beneficial for GBM patients. Methods. We performed the largest drug combination screen to date in GBM, using a high-throughput effort where we selected 90 drug combinations for their activity onto 25 patient-derived GBM cultures. 43 drug combinations were selected for interaction analysis based on their monotherapy efficacy and were tested in a short-term (3 days) as well as long-term (18 days) assay. Synergy was assessed using dose-equivalence and multiplicative survival metrics. Results. We observed a consistent synergistic interaction for 15 out of 43 drug combinations on patient-derived GBM cultures. From these combinations, 11 out of 15 drug combinations showed a longitudinal synergistic effect on GBM cultures. The highest synergies were observed in the drug combinations Lapatinib with Thapsigargin and Lapatinib with Obatoclax Mesylate, both targeting epidermal growth factor receptor and affecting the apoptosis pathway. To further elaborate on the apoptosis cascade, we investigated other, more clinically relevant, apoptosis inducers and observed a strong synergistic effect while combining Venetoclax (BCL targeting) and AZD5991 (MCL1 targeting). Conclusions. Overall, we have identified via a high-throughput drug screening several new treatment strategies for GBM. Moreover, an exceptionally strong synergistic interaction was discovered between kinase targeting and apoptosis induction which is suitable for further clinical evaluation as multi-targeted combination therapy.
AB - Background. IDH-wildtype glioblastoma (GBM) is a highly malignant primary brain tumor with a median survival of 15 months after standard of care, which highlights the need for improved therapy. Personalized combination therapy has shown to be successful in many other tumor types and could be beneficial for GBM patients. Methods. We performed the largest drug combination screen to date in GBM, using a high-throughput effort where we selected 90 drug combinations for their activity onto 25 patient-derived GBM cultures. 43 drug combinations were selected for interaction analysis based on their monotherapy efficacy and were tested in a short-term (3 days) as well as long-term (18 days) assay. Synergy was assessed using dose-equivalence and multiplicative survival metrics. Results. We observed a consistent synergistic interaction for 15 out of 43 drug combinations on patient-derived GBM cultures. From these combinations, 11 out of 15 drug combinations showed a longitudinal synergistic effect on GBM cultures. The highest synergies were observed in the drug combinations Lapatinib with Thapsigargin and Lapatinib with Obatoclax Mesylate, both targeting epidermal growth factor receptor and affecting the apoptosis pathway. To further elaborate on the apoptosis cascade, we investigated other, more clinically relevant, apoptosis inducers and observed a strong synergistic effect while combining Venetoclax (BCL targeting) and AZD5991 (MCL1 targeting). Conclusions. Overall, we have identified via a high-throughput drug screening several new treatment strategies for GBM. Moreover, an exceptionally strong synergistic interaction was discovered between kinase targeting and apoptosis induction which is suitable for further clinical evaluation as multi-targeted combination therapy.
KW - EGFR/ERBB2/BCL2/MCL1
KW - IDH-wildtype glioblastoma (GBM)
KW - drug combination screen
KW - multi-target therapy
KW - synergistic drug combinations
UR - http://www.scopus.com/inward/record.url?scp=85167415746&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/noajnl/vdad073
DO - https://doi.org/10.1093/noajnl/vdad073
M3 - Article
C2 - 37455945
SN - 2632-2498
VL - 5
JO - Neuro-oncology advances
JF - Neuro-oncology advances
IS - 1
ER -