Researchers discover promising approach against treatment-resistant cancer

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Photo: Albert Einstein College of Medicine 

Researchers at Albert Einstein College of Medicine have devised a promising strategy for overcoming a key cause of cancer deaths: the ability of cancer cells to thrive in the face of chemotherapy drugs designed to destroy them.  

There are cells, called cancer stem cells, that have the ability to evade chemotherapy and lie dormant for a while. But later they can become active again, generate more cancer cells, and cause relapses.  

Published in the March 7 issue of Nature Communications, investigators used a two-drug combination to achieve chemotherapy’s goal: to make cancer cells self-destruct via the biological process known as apoptosis—also known as programmed cell death. 

The treatment worked against human cancer cell lines that resisted apoptosis despite exposure to different types of chemotherapy, and against apoptosis-resistant human tumors implanted in mice. 

“We need new, broadly active therapies that can attack a range of cancers while causing fewer side effects than current treatments, and we hope our new therapeutic strategy will prove to be a viable option,” said Evripidis Gavathiotis, PhD, professor of biochemistry and of medicine at Einstein and corresponding author on the paper. 

How Apoptosis Works 

The body relies on apoptosis for getting rid of unwanted cells, including damaged cells that need to be removed so they don’t develop into cancer cells. Both chemotherapy and radiation rely on damaging cancer cells so they undergo apoptosis, but that doesn’t always happen. 

Every cell in the body contains some two dozen apoptotic proteins that promotes its own destruction. Some proteins stimulate apoptosis (pro-apoptotic proteins), while others block the process (anti-apoptotic proteins).  

BAX—The Executioner Protein

The new drug combination discovered by researchers at Einstein kills apoptosis-resistant cancer cells by boosting the active form of one pro-apoptotic protein in particular: BAX, dubbed the “executioner protein.” They then combined that with Navitoclax, an investigational  cancer drug that blocked the activity of proteins that inhibit the effectiveness of BAX. 

When the Einstein team tested the drug duo against 46 human blood and solid tumor cell lines, it packed a one-two punch, boosting active BAX to toxic levels in cancer cells, and Navitoclax acting as BAX’s bodyguard by preventing other proteins from neutralizing BAX. 

Limiting Side Effects 

The two orally-administered drugs were then tested in mice implanted with tumor cells from a colorectal-cancer cell line that had resisted one version of BAX and Navitoclax as individual drugs but had succumbed to their combined use. The in vivo experiment produced similar results.  

Individually, each drug had limited effectiveness in reducing tumor growth, while combining them significantly suppressed tumor growth, indicating that the two drugs act synergistically to defeat apoptosis-resistant tumors. 

“Equally important, mice receiving the two-drug combination tolerated it remarkably well,” noted Dr. Gavathiotis. “Moreover, analysis of the treated mice showed that healthy cells were not affected by the two-drug combination—likely making it safer than standard chemotherapies, which are toxic to all dividing cells, both cancerous and normal.” 

Read the source article here.