Even Cancer Gets Stressed Out

The biggest challenge in treating advanced prostate cancer is that it develops resistance to hormonal therapy and cancer-fighting drugs. “In fact, advanced cancers have been shown to be able to become resistant to any therapy that is applied,” says Robert Getzenberg, Ph.D., The Donald S. Coffey Professor of Urology and the Brady’s Director of Research. The answer, he believes, is “not necessarily to keep developing new therapies,” but to look for hidden weaknesses. In other words, says Getzenberg, “Does the cancer sacrifice anything in order to become so adept at defying treatment?” One thing that seems to go out the window, at least in prostate cancer, is tolerance to stresses in the environment. Imagine any movie in which the characters are in a tight spot — say, on a cramped WWII submarine riding out depth charges. What happens? People start snapping at each other; they don’t cope well; maybe they make poor decisions. The pressure gets to them.

Imagine any movie in which the
characters are in a tight spot.
What happens? People start
snapping at each other. They don’t
cope well. Maybe they make poor
decisions. The pressure gets to
them. This happens to cancer, too.

Apparently, cancer can get stressed out. In studies that were recently published in the Journal of Cellular Biochemistry, Youqiang Li, a scientist in Getzenberg’s laboratory, compared prostate cancer cells that had become resistant to chemotherapy to those that still responded to it, and found that the resistant cells were sensitive to stresses in their environment. “Stresses such as heat and inadequate food had a much bigger impact on these resistant cells,” notes Getzenberg.

Is it possible that we could somehow kick cancer when it’s down? These studies point to new avenues of treatment where an environmental stress can be added to make traditional therapy more effective. As it happens, one highly promising example of this type of approach, called TEMT (thermal enhanced metastatic therapy), is being developed here at Hopkins. The idea is to make hidden, metastatic prostate cancer cells more sensitive to treatment with the use of a powerful weapon: Heat.

“Heating cancer cells makes them more vulnerable to radiation, chemotherapy, and immunotherapy,” says Getzenberg. The idea for TEMT began with Getzenberg’s predecessor as Brady Research Director, legendary scientist Don Coffey, Ph.D., who learned that heating a cell changes the makeup of its DNA, and weakens its internal structure. Hopkins scientists including Shawn Lupold, Robert Ivkov, Prakash Kulkarni, Coffey, Getzenberg, Ted DeWeese and colleagues are working hard to learn how best to exploit this chink in cancer’s armor.

In related news from Getzenberg’s laboratory:

3-D “Habitats” for Prostate Cancer Habitat.
The name conjures up a glass tank with a hamster wheel in it; and yet, maybe this is what we need, to learn how prostate cancer cells truly operate. Much of what we know about the molecular basis of prostate cancer comes from what scientists have observed in the Petri dish — cells, obtained from prostate cancer specimens, cultured in little, fl at containers. “This is certainly not how these cells survive and grow,” says Getzenberg, “either within the prostate, or at other sites in the body.”

Thus, in hopes of building a more realistic “habitat” that reflects how prostate cancer cells really live and grow, Getzenberg and colleagues here at the Brady have joined forces with Robert Austin, a physicist at Princeton University, and his team. They have studied the behavior of prostate cancer cells — ranging from the less invasive to the most aggressive strains — in specially built microchambers. “These miniature chambers have many small mountains within them, and the ability of the cancer cells to climb these mountains and establish camp at the top appears to correlate with the metastatic ability of the cells,” says Getzenberg. Think about it: If you want to study a fearsome tiger at the zoo, will you learn more from the one stuck in a cage, or the one that has enough room to roam?

If you want to study a fearsome
tiger at the zoo, will you learn
more from the one stuck in a cage,
or the one that has enough room
to roam?

“These novel 3-D model systems are unique tools that may give us a better understanding of the molecular mechanisms through which these cells actually grow and invade other cells,” Getzenberg adds. This work was published in the Proceedings of the National Academy of Sciences, and was supported with a grant from the National Cancer Institute, Physical Sciences and Oncology Center.

A Marker for Aggressive Cancer?
In other work, Getzenberg and colleagues George Netto, Elizabeth Platz, Naoki Terada, Prakash Kulkarni, Alan Partin, and Leslie Mangold, have focused on a protein called Cyr61, which may turn out to be a marker of aggressive cancer. After studies of the protein in tissue samples appeared promising, the scientists demonstrated that Cyr61 could be detected in the blood of men with prostate cancer, “and that it may have some ability to characterize the aggressiveness of prostate tumors,” notes Getzenberg. “These studies need to be confi rmed with additional samples, but we have shown that Cyr61 represents a unique change found in both tissue and blood. We hope that one day, it will serve as part of a panel of markers that may help us characterize the nature of a man’s prostate cancer.” Some of this work was published in the journal, Clinical Cancer Research.


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