Eradication of ENO1-deleted Glioblastoma through Collateral Lethality [article]

Yu-Hsi Lin, Nikunj Satani, Naima Hammoudi, Jeffrey J Ackroyd, Sunada Khadka, Victoria C Yan, Dimitra K Georgiou, Yuting Sun, Rafal Zielinski, Theresa Tran, Susana Castro Pando, Xiaobo Wang (+16 others)
2018 bioRxiv   pre-print
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
more » ... ) 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.
doi:10.1101/331538 fatcat:prgokqujsnbbzdsl3s4ynsseh4