Small-molecule enolase inhibitor found to be effective in killing brain cancer cells that were missing ENO1, one of two genes encoding the enolase enzyme, as per the study by the team of researchers at the University of Texas MD Anderson Cancer Center, published in Nature Metabolism.
The new study provide the concept of collateral lethality, in which a vital protein is lost through genetic deletion as a bystander near a tumor suppressor gene, and a redundant protein is blocked therapeutically.
"Collateral lethality could expand the scope of precision oncology beyond activated oncogenes, and allow targeting of genomic deletions, largely considered un-actionable," said corresponding author Florian Muller, Ph.D., assistant professor of Cancer Systems Imaging and Neuro-Oncology.
Enolase encoding genes ENO1 and ENO2, encode slightly different. Targeting only ENO2 is attractive as it allows for the selective treatment of cancer cells missing ENO1.
The research team worked to generate an enolase inhibitor, called HEX, that targets ENO2 over ENO1. Prodrug POMHEX was developed, which is biologically inactive until it is metabolized into HEX within cells.
Treatment with POMHEX blocked glycolysis, inhibited cell growth and stimulated cell death. Conversely, treatment of cells with normal ENO1 showed minimal effects. Further, in animal models of ENO1-deficient tumors, both HEX and POMHEX treatment was well- tolerated and effectively blocked tumor growth relative to controls, with some instances of complete tumor eradication.
Taking the work one step further, the team demonstrated that the best effective dose could be safely given in multiple models, suggesting favorable future translation to the clinical studies.
"We were encouraged by the promising preclinical activity of these novel enolase inhibitors and that the safety profile extends to higher models. While there could be further refinements, I am optimistic that even HEX would show significant clinical activity against ENO1-deleted cancers," Muller said.
ENO1 deletions also occur in liver cancer, bile duct cancer and large-cell neuroendocrine lung cancers, all of which share poor prognosis and limited treatment options, Muller explained. Thus, once an optimal therapy candidate has been developed, there is potential to evaluate the ENO2 inhibitor in treating patients with multiple cancer types.