September 23, 2014

   A Publication of the James Buchanan Brady
   Urological Institute Johns Hopkins Medical Institutions

Volume II, Autum 2005

How Some Cancer Survives Deadly Attack

What is prostate cancer’s secret weapon? What allows it to survive an onslaught of the most lethal chemotherapy drugs known to science? Why, if such drugs are akin to amini-nuclear blast, do a few cells manage to stagger out of the mushroom cloud, and start growing again?

This is called “therapeutic resistance, ”and it’s one of the biggest challenges facing men with advanced prostate cancer, and the doctors working to treat it. Prostate cancer succeeds, in large part, by sheer diversity, Its cells are notoriously heterogeneous — which means that each cell can respond differently to the same type of therapy. This differential response is the ultimate culprit that causes cancer to turn aggressive, as the milder cancer cells are killed, and the tougher ones — the ones resistant to further therapy — survive.

The most lethal drugs are like amini-nuclear blast to cancer. And yet,a few cells manage to stagger out of the mushroom cloud,and start growing again.

Jun Luo, Ph.D., assistant professor ofu rology, wants to figure out what’s in the hardiest cells’ survival kits. What do they need, or what do they do, so they can survive in the cytotoxic environment created by the cell-killing drugs? As a basic scientist, he is particularly interested in how cancer cells sense the danger, make last-minute adjustments, repopulate, and thrive. With funding help from The Peter Jay Sharp Foundation, he is focusing on a particular part of the cell, called the endoplamic reticulum (ER), which is responsible for the folding and maturation of proteins that will eventually be secreted outside the cell.

“The ER is very sensitive to environmental changes,” Luo explains, “and may be the sensor that determines the survivability ofthe cancer cells.” Like a military bunker in wartime, the ER is chock-full of sensors, and functions to keep the cell alive even when it’s under attack. “Characterizing the key molecular sensors will give us new targets for advanced therapeutics that can disrupt the adaptive strategies that cancer cells use to survive treatment.” Luo believes that these sensors may be moving targets — that, like emergency batteries, they switch on and off, and probably provide just the immediate and transient relief that cancer cells need to survive the therapy. His challenge now is to catch them in the act.

Working on a molecular level, Luo is using cutting-edge technologies such as microarray to investigate the machinery that enables cancer cells to respond and adapt to stress. His results are promising: Already, Luo has found a molecule, named AGR2, that is massively over-produced in cancer cells subjected to the toxic stress that happens in chemotherapy. This molecule is quickly sensed by the ER. Luo has also found that this molecule is over-produced in human prostate cancer tissues.

Luo’s work, says Patrick C. Walsh, M.D., University Distinguished Professor of Urology, “proves that cancer cells have acquired the readiness to respond and adapt to stress conditions caused by the therapeutic drugs.While there is much work to do to follow this important lead, the basic concept is starting to bear fruit.” The next step is to design with this “secret weapon” in mind — to target and disable the adaptive response pathway that cancer cells use to evade primary therapy.

 

 

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