RT Journal Article
SR Electronic
T1 Eradication of <em>ENO1</em>-deleted Glioblastoma through Collateral Lethality
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 331538
DO 10.1101/331538
A1 Yu-Hsi Lin
A1 Nikunj Satani
A1 Naima Hammoudi
A1 Jeffrey J. Ackroyd
A1 Sunada Khadka
A1 Victoria C. Yan
A1 Dimitra K. Georgiou
A1 Yuting Sun
A1 Rafal Zielinski
A1 Theresa Tran
A1 Susana Castro Pando
A1 Xiaobo Wang
A1 David Maxwell
A1 Zhenghong Peng
A1 Federica Pisaneschi
A1 Pijus Mandal
A1 Paul G. Leonard
A1 Quanyu Xu
A1 Qi Wu
A1 Yongying Jiang
A1 Barbara Czako
A1 Zhijun Kang
A1 John M. Asara
A1 Waldemar Priebe
A1 William Bornmann
A1 Joseph R. Marszalek
A1 Ronald A. DePinho
A1 Florian L. Muller
YR 2018
UL http://biorxiv.org/content/early/2018/05/25/331538.abstract
AB Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We recently demonstrated that SF2312, a natural product phosphonate antibiotic, is a potent inhibitor of the glycolytic enzyme Enolase with potential utility for the collateral lethality-based treatment of Enolase-deficient glioblastoma (GBM). However, phosphonates are anionic at physiological pH, limiting cell and tissue permeability. Here, we show that addition of pivaloyloxymethyl (POM) groups to SF2312 (POMSF) dramatically increases potency, leading to inhibition of glycolysis and killing of ENO1-deleted glioma cells in the low nM range. But the utility of POMSF in vivo is dose-limited by severe hemolytic anemia. A derivative, POMHEX, shows equipotency to POMSF without inducing hemolytic anemia. POMHEX can eradicate intracranial orthotopic ENO1-deleted tumors, despite sub-optimal pharmacokinetic properties. Taken together, our data provide in vivo proof-of-principal for collateral lethality in precision oncology and showcase POMHEX as a useful molecule for the study of glycolysis in cancer metabolism.