To disrupt cancer growth, 2 Pittsburgh labs try cutting its fuel
Two UPMC labs are quietly breaking ground in the basic science of telomeres, parts of cells that play a central role in how cancer spreads.
Research in the field gets far less attention than headline-grabbing developments in immunotherapy but could play a key role in the search for cancer cures.
Telomeres sit at the ends of chromosomes, the gene packets that cells replicate during division and growth. They protect chromosomes in the way the plastic caps at the ends of shoelaces protect the laces, said Roddy O'Sullivan, head of one of the University of Pittsburgh Cancer Institute labs studying telomeres. Telomeres shorten each time cells divide, and when they become too short, cells die.
Cells that divide with the greatest frequency in the human body — such as stem, bone marrow and gut cells — produce an enzyme that counteracts the shortening, preserving the telomeres and the cells in which they reside. Many cancers also pump out the enzyme, known as telomerase, fueling the uncontrolled growth that is characteristic of the disease.
Without the ability to lengthen telomeres, cancers would likely die, O'Sullivan said.
“These cancer cells have cunningly taken something that's very beneficial, very useful for the cells, and turned it into something bad,” he said.
The labs of O'Sullivan and Patricia Opresko, another UPCI biochemist, each published papers in academic journals this month describing new findings about how telomeres and telomerase work. What they are learning could help both to kill cancer cells and preserve life-giving cells — a branch of study that has fueled speculations on immortality.
Cancer immunotherapy, which focuses on equipping the body's immune system to better fight the disease, has received the most attention in recent years as a way to treat cancer, and is a centerpiece of the federal “moonshot” program to accelerate the search for cures. Telomere science is less advanced, but researchers say it shows promise on the road to cures.
Opresko's lab for the last four years has been studying a way of stopping telomere growth. She has been bombarding parts of cells with free radicals, the harmful atoms that can be generated from smoking, stress and other environmental factors. Free radicals cause oxidative stress, a process that is known to hamper telomere growth.
Researchers expected that blasting telomeres with free radicals would stop the growth, but it didn't. So they directed the atoms instead at the DNA building blocks that cells stitch together to lengthen telomeres, using the enzyme telomerase. That stopped the growth, Opresko said.
Opresko's lab studied the technique in cancer cells in petri dishes. The results of her work were published this month in the journal Nature Structural and Molecular Biology. The results suggest that oxidative stress, if directed at the DNA building blocks in cancer cells, might be able to stop some cancers' growth.
That is a long way off. The next step likely would be tests in rodents or other animals, followed eventually by human tests, she said.
Cancers have other defenses too. They produce an enzyme that removes the damaged DNA building blocks, promoting telomere growth. Opresko's study suggests that cancers with short telomeres might be more susceptible to oxidative stress than those with longer telomeres. Future research could seek to home in on which cancer cells have short telomeres and which have long ones, to focus treatments where they might be most effective.
“We're hoping the clues we discover in trying to advance fundamental knowledge about biology could be taken advantage of to develop new therapies,” Opresko said.
While most cancers produce telomerase, about 15 percent lengthen their telomeres by another process, known as alternative lengthening of telomeres, or ALT. Those cancers, some of the most aggressive, are among the ones O'Sullivan studies.
Researchers don't know much about ALT, including whether cancer cells that once produced telomerase can start to use ALT if they lose the ability to produce the enzyme, O'Sullivan said.
He published a study this month in the journal Cell Reports identifying 139 proteins that are uniquely associated with the process. Many of the proteins had not been associated with one another before his study, he said. His lab has published the list and plans to keep studying the relationships between the proteins with an eye to disrupting cancer's growth.
“The idea is that … you want to find the one or two at the very base of this tree — when you hit those, the whole thing falls apart,” O'Sullivan said.
Jan Karlseder, director of the Glenn Center for Aging Research at the Salk Institute for Biological Studies, has awaited O'Sullivan's results.
“They surprised me in a positive way, because it really contributes to our understanding of these pathways,” Karlseder said.
The results are a significant step forward, he said.
“The more we understand these pathways, the better the chances become that we can target them,” he said.
On the flip side, knowing more about cancer's unlimited growth could one day help heal damaged noncancer cells, which are linked to a long list of age-related health problems, the UPCI researchers said.
But that tangent has dangers, too, O'Sullivan said. Extending the lives of all cells would impair the body's ability to terminate damaged cells, which could give rise to harmful mutations that are more resilient.
“Evolution has not selected us to live forever,” he said.
Wes Venteicher is a Tribune-Review staff writer. Reach him at 412-380-5676 or firstname.lastname@example.org.