(photo credit: INGIMAGE)
Researchers at Bar-Ilan University have identified an enzyme that supports the survival and dissemination of metastatic cancer cells, and developed a synthetic compound that targets it and kills the proliferating cells in mice.
Prof. Uri Nir, of the Faculty of Life Sciences at the university in Ramat Gan, and colleagues have just published their research in the journal Nature Communications.
Malignancies can be treated more successfully when confined to one organ, but when cancer cells spread into other parts of the body, the battle is much more difficult. Although immunotherapy can be effective in treating the metastatic phase of the disease, it is still applicable to a small number of patients.
When leaving the primary tumor, cancer cells have greater tools to survive in very harsh conditions, such as a shortage of basic nutrients such as glucose. Metastatic cells can safeguard against this metabolic deficiency by reprogramming their energy generation system.
The team found the existence of the enzyme, called FerT, in the energy-generating mitochondria of that cancer cells that they couldn’t find in the mitochondria of normal cells. When they targeted the enzyme in the lab, the malignant cells failed to produce energy and died. The team then began searching for the enzyme elsewhere in the body and detected it in only one specific cell – none other than sperm cells
Sperm cells are the only cells in the body that exert their functions outside the body. “Like metastatic cells, sperm cells are unique in that they can also generate energy under very harsh conditions. Once they have entered the female birth canal, where there is no blood supply for them, they produce and expend enormous amounts of energy under very extreme or abnormal conditions,” explained Nir. “We found that very aggressive metastatic cancer cells looked for and identified this sperm-specific protein, learned how to produce it and harnessed it to increase the power of their mitochondria and produce energy under very harsh conditions. We have shown that not only do sperm initiate life, but also carry with them the potential to terminate life.”
Using advanced chemical and robotic approaches, the team developed a synthetic compound that can be given orally or by injection to animals or humans. When applied to metastatic cells in culture or mice with metastatic tumor, the compound – called E260 – enters the metastatic cells and then into the mitochondria. It then binds the enzyme FerT, distorts its activity and – not only inhibits its activity, but as a result of the inhibition – causes a complete collapse of the entire mitochondria power station. They hope to pursue Phase 1 clinical trials within 18 months.
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Metastatic cells are very capable, noted Nir. When they identify the damage to the mitochondria power station they start to activate a recycling process (called autophagy) aimed at decomposing and rebuilding mitochondria. This recycling process, however, requires a lot of energy and this ongoing energy consumption leads to a severe energy depletion, metabolic crisis and death of the metastatic cells. “We have treated mice with metastatic cancer, and this compound completely cured them with no adverse or toxic affect that we can see. We have also checked several normal cells and they are not affected,” said Nir.
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