TY - JOUR
T1 - DIVERSet JAG Compounds Inhibit Topoisomerase II and Are Effective Against Adult and Pediatric High-Grade Gliomas
AU - Howarth, Alison
AU - Simms, Claire
AU - Kerai, Nitesh
AU - Allen, Olivia
AU - Mihajluk, Karina
AU - Madureira, Patricia A.
AU - Sokratous, Giannis
AU - Cragg, S.
AU - Lee, Sang Y.
AU - Morley, Andy D.
AU - Keyoumars, Ashkan
AU - Cox, Paul A.
AU - Pilkington, Geoffrey J.
AU - Hill, Richard
N1 - Funding Information:
We thank all patients and staff in procuring samples and Kings College Hospital NHS Foundation Trust. Dr. Val Millar (Target Discovery Institute, University of Oxford) provided assistance with high content image analysis. Research is core funded by Brain Tumour Research. A. H. is supported by the Ollie Young Foundation. P. A. M. is funded by FCT Investigator contract from the Foundation for Science and Technology (FCT), Portugal (ref: IF/00614/2014) and FCT exploratory grant, ref.: IF/00614/2014/CP12340006. C. B. M. R. is financed by FCT Research Center Grant ref.: UID/BIM/04773/2013CBMR1334. A. H. C. S. N. K. K. M. S. C. P. M. P. C. and R. H. performed the experiments; G. S. and A. K. obtained and provided clinical material and data; R. H. designed the study; S. Y. L. and A. M. conducted the DIVERset library screen; A. H. N. K. G. P. A. M. P. C. and R. H. interpreted the data. R. H. wrote the manuscript, and all authors checked and revised the final paper. Opal Oncology Ltd. (A. Morley) has filed a patent relating to JAG agents described in this work to the Intellectual Property Office (United Kingdom). All other authors declare no potential conflict of interest.
Funding Information:
Research is core funded by Brain Tumour Research . A. H. is supported by the Ollie Young Foundation . P. A. M. is funded by FCT Investigator contract from the Foundation for Science and Technology (FCT), Portugal (ref: IF/00614/2014 ) and FCT exploratory grant, ref.: IF/00614/2014/CP12340006 . C. B. M. R. is financed by FCT Research Center Grant ref.: UID/BIM/04773/2013CBMR1334 .
Publisher Copyright:
© 2019 The Authors
PY - 2019/10
Y1 - 2019/10
N2 - High-grade gliomas (HGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis in both adult and pediatric patients. Clinical response is compounded by resistance to standard frontline antineoplastic agents, an absence of novel therapeutics, and poor in vitro models to evaluate these. We screened a range of recently identified anticancer compounds in conventional adult, pediatric, and new biopsy-derived HGG models. These in vitro lines showed a range of sensitivity to standard chemotherapeutics, with varying expression levels of the prognostic markers hypoxia-induced factor (HIF) 1α and p53. Our evaluation of lead DIVERSet library compounds identified that JAG-6A, a compound that was significantly more potent than temozolomide or etoposide, was effective against HGG models in two-dimensional and three-dimensional systems; mediated this response by the potent inhibition of topoisomerase Iiα; remained effective under normoxic and hypoxic conditions; and displayed limited toxicity to non-neoplastic astrocytes. These data suggest that JAG-6A could be an alternative topoisomerase IIα inhibitor and used for the treatment of HGG.
AB - High-grade gliomas (HGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis in both adult and pediatric patients. Clinical response is compounded by resistance to standard frontline antineoplastic agents, an absence of novel therapeutics, and poor in vitro models to evaluate these. We screened a range of recently identified anticancer compounds in conventional adult, pediatric, and new biopsy-derived HGG models. These in vitro lines showed a range of sensitivity to standard chemotherapeutics, with varying expression levels of the prognostic markers hypoxia-induced factor (HIF) 1α and p53. Our evaluation of lead DIVERSet library compounds identified that JAG-6A, a compound that was significantly more potent than temozolomide or etoposide, was effective against HGG models in two-dimensional and three-dimensional systems; mediated this response by the potent inhibition of topoisomerase Iiα; remained effective under normoxic and hypoxic conditions; and displayed limited toxicity to non-neoplastic astrocytes. These data suggest that JAG-6A could be an alternative topoisomerase IIα inhibitor and used for the treatment of HGG.
UR - http://www.scopus.com/inward/record.url?scp=85069805072&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069805072&partnerID=8YFLogxK
U2 - 10.1016/j.tranon.2019.07.007
DO - 10.1016/j.tranon.2019.07.007
M3 - Article
C2 - 31374406
AN - SCOPUS:85069805072
SN - 1944-7124
VL - 12
SP - 1375
EP - 1385
JO - Translational Oncology
JF - Translational Oncology
IS - 10
ER -
