Novel targeted therapy blocks critical metabolic pathways in cancer cells

Scientists from The University of Texas MD Anderson Cancer Center have designed a new targeted therapy, known as POMHEX, which inhibits vital metabolic pathways in tumor cells containing specific genetic defects.

Novel targeted therapy blocks critical metabolic pathways in cancer cells
Florian Muller, PhD. Image Credit: The University of Texas M. D. Anderson Cancer Center.

The small-molecule enolase inhibitor was identified in preclinical studies and was found to be effective in destroying brain cancer cells that lacked ENO1—one of the two genes that encode the enolase enzyme.

Published recently in the Nature Metabolism journal, the study results give proof of principle for a treatment approach called collateral lethality. In this method, a crucial protein is lost via genetic deletion as a bystander close to a tumor suppressor gene, and a redundant protein is also inhibited therapeutically.

Collateral lethality could expand the scope of precision oncology beyond activated oncogenes, and allow targeting of genomic deletions, largely considered un-actionable. Our work provides proof of principle that this approach can actually work with a drug in animal models.”

Florian Muller, PhD, Study Corresponding Author and Assistant Professor of Cancer Systems Imaging and Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center

Enolase is a crucial enzyme that plays a role in glycolysis—a metabolic pathway that is increased in several types of cancers to stimulate their increased cell growth.

ENO1 and ENO2 are two kinds of genes that encode somewhat different but redundant models of the enolase enzyme, and many cancers, like glioblastoma, lack the ENO1 gene due to chromosomal loss. This leaves the tumor cells with only the ENO2 gene to continue the glycolysis process, rendering the cancer cells extremely sensitive to enolase inhibitors, explained Muller.

Although therapies targeting both kinds of enolase enzymes have already been developed, inhibiting the ENO1 gene can cause unnecessary side effects in standard cells. Hence, targeting the ENO2 gene is particularly attractive, because it enables the selective treatment of tumor cells that lack the ENO1 gene.

Therefore, the researchers worked together to create an enolase inhibitor, known as HEX, that preferentially targets the ENO2 gene over ENO1. They created the prodrug, called POMHEX, to enhance the drug’s potential to penetrate cells. POMHEX is biologically inactive before it is metabolized into HEX inside the cells.

In cancer cell lines that lack the ENO1 gene, POMHEX therapy inhibited cell growth, blocked glycolysis, and triggered cell death. On the other hand, cells treated with standard ENO1 exhibited minimal effects.

Additionally, in animal models of ENO1-deficient tumors, POMHEX as well as HEX treatments were well-tolerated and successfully inhibited the growth of tumor cells relative to controls, with some cases of complete tumor elimination.

Taking the study one step further, the researchers showed that the therapeutically effective dose can be safely introduced in numerous models, indicating favorable upcoming 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.”

Florian Muller, PhD, Study Corresponding Author and Assistant Professor of Cancer Systems Imaging and Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center

Moreover, deletions of the ENO1 gene happen in bile duct cancer, liver cancer, and large-cell neuroendocrine lung cancers, which collectively share poor prognosis and have reduced treatment options, explained Muller.

Hence, as soon as an optimal candidate has been designed, there is a possibility to assess the ENO2 inhibitor in treating patients with several types of cancers.

Source:
Journal reference:

Lin, Y-H., et al. (2020) An enolase inhibitor for the targeted treatment of ENO1-deleted cancers. Nature Metabolism. doi.org/10.1038/s42255-020-00313-3.

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