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Scientists uncover a better way to kill cancer cells

March 5, 2020

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Sunnybrook research suggests a new chemotherapy drug approach may be more effective than current methods and could offer new hope to some cancer patients.

“New exciting drugs are being developed in the treatment of cancer, but how best to target a specific protective mechanism of cells in the quest to destroy cancer cells, has remained unclear for pharma and medicine,” says Dr. David Andrews, senior author of a new paper published in Molecular Cell and director of Biological Sciences at Sunnybrook Research Institute (SRI). “We believe we’ve found an answer.”

A major target for a new class of targeted drugs are “guardian proteins”, whose role is to stop or slow down programmed cell death. Guardian proteins are one of three groups of proteins that do a little dance to regulate cell death; in other words, the fate of the cell is determined by the interplay of these three types of proteins. Unlike most normal cells, cancer cells depend on high levels of these guardian proteins for their survival. One approach to cancer treatment is to target cancerous cells and trigger the process the guardian proteins are trying to prevent: the programmed death of a cell.

All cells in the body are hardwired to kill themselves if things go wrong. Most chemotherapy works by damaging cells. As cancer cells are already damaged and have a lower threshold to additional damage, they turn on programmed cell death and kill themselves, while normal cells have a higher reserve capacity for stress and do not turn on the programmed cell death pathway. Recently the pharmaceutical industry has made great progress designing drugs like venetoclax that compete with the two types of proteins that trigger programmed cell death; so when a drug binds a guardian protein, it displaces a protein that then turns on programmed cell death.

“We have shown there is another way to target the guardian proteins so that they no longer inhibit the proteins that turn on cell death,” says co-lead author Dr. Christian Bogner, who was a post-doctoral fellow at SRI at the time the paper was developed and is now a clinician scientist at the Technical University of Munich.

“With our new approach, the proteins that turn on cell death are activated to do so while still bound to the guardian protein that normally shuts them off,” says co-lead author Dr. Justin Kale, a post-doctoral fellow at SRI. “This means it will be much harder for resistance mechanisms to develop than it would be for the current class of competitive inhibitors like venetoclax.”

A drug that works this new way is called an allosteric inhibitor. It enables a switch-like activation of a part of the programmed cell death process when targeting cancer cells, dramatically enhancing the cell death process. Additional benefits: less drug will be required, and it will act more quickly.

“Our results suggest that it should be possible to make an anti-cancer drug that can release the brakes on programmed cell death so they no longer inhibit the proteins that turn on cell death,” adds Dr. Andrews, also a Professor in the departments of Biochemistry and Medical Biophysics at University of Toronto. “Our findings also suggest ways to improve the use of existing drugs.”

Read the full paper in Molecular Cell »