Cancer metastasis and drug chemoresistance constitutes a major source of morbidity and mortality despite significant progress in treatments for cancer. The initiation of the migration cascade of cancer metastasis is accompanied by alternation in cells properties, a process which is regulated by the epithelial-mesenchymal transition (EMT) cellular program.
The present invention introduces a novel concept in which metabolites have an active role as inhibitors of this program and provides a set of new targets for inhibiting tumor progression.
Prof. Shaul’s lab identified a set of genes encoding metabolic enzymes that produce “suppressor metabolites” that are involved in the formation of metastasis.
The group found that glutathione peroxidase 8 (GPX8), an enzyme that resides in the endoplasmic reticulum, is an essential regulator of tumor aggression.
The knockout of this enzyme in animal models, downregulated the EMT characteristics, and resulted in loss of cancer stemness features. In addition, the knockout significantly delayed tumor initiation and decreased its growth rate.
The proliferation rate of cancer cells requires synthesis of building blocks produced by metabolic enzymes. The group presents a set of newly identified metabolic enzymes that regulate cancer aggressiveness.
These enzymes can serve as new targets for treating cancer as their function can overcome the resistance to current therapy. Treating cancer patients with standard anti-cancer drugs together with inhibition of metabolic enzymes, such as GPX8, will increase the drugs efficiency and will prevent the formation of metastatic dissemination.
For more information regarding GPX8:
Proc Natl Acad Sci U S A 2020 Sep 1;117(35):21420-21431.
doi: 10.1073/pnas.2010275117. Epub 2020 Aug 18.