October 15, 2012
By By David Martin
|Shane Stecklein earned his Ph.D. and is now completing his medical education.|
"The fight against cancer" is not just an expression. Oncologists treat the disease by destroying the DNA of cancer cells. The goal is to do irreparable harm.
And at the University of Kansas Medical Center, a student has discovered a potential method for knocking down a class of cancer-associated genes, which may lead to better treatments for breast and ovarian cancers.
Cancer doctors use radiation and chemotherapy to clobber DNA. But some cancers can be difficult to treat because gene-encoded proteins will come in behind the therapies and begin to undo the desired damage. Shane Stecklein, Ph.D., an M.D./Ph.D. student in the KU School of Medicine, is the lead author of a recent paper in Proceedings of the National Academy of Sciences describing a means by which a drug that's in clinical trials may enhance current treatments.
Women who inherit a mutation in their BRCA1 and BRCA2 genes have a much greater risk of developing breast, ovarian and other cancers. Normal BRCA genes actually work to suppress tumors. They accomplish this by repairing breaks in DNA strands, in effect preventing the accumulation of mutations that incite cancerous growth.
For women with non-hereditary breast or ovarian cancer, which is much more common than the inherited kind, BRCA genes' abilities to fix damaged DNA can be problematic. By doing what they're supposed to do — repair damage — the genes blunt the effectiveness of radiation and chemotherapy. In short, they fix what isn't meant to be fixed.
"BRCA1 is a good gene and is necessary to prevent normal cells from becoming cancerous," says Stecklein. "But in a cancer cell, BRCA1 actually screws up what we're trying to accomplish with therapy."
Roy Jensen, M.D., director of The University of Kansas Cancer Center and senior author of the study, says the discovery has "a lot of potential in the clinic."
Thrill of the chase
Stecklein's first experience with cancer research came when he was an undergraduate student at KU. While researching colon cancer under Kristi Neufeld, Ph.D., an associate professor of molecular biosciences, he decided that he wanted to become a physician-scientist and to specialize in oncology.
Stecklein says he is fascinated by cancer's mysteries. "We don't have any of the answers yet," he says. "There's a tremendous need to understandthese diseases on a much more fundamental level so that we can identify and target their weaknesses. It's the thrill of the chase."
Jensen arrived at KU at the time Stecklein was applying to medical schools. Jensen's research focus is breast cancer, and he is an internationally recognized expert on BRCA1. Stecklein decided to "switch tissues" -- from colon to breast -- when the opportunity arose to work in Jensen's lab.
"He's a kid who just really loves science and loves being at the bench," Jensen says of Stecklein. "He's just happy as a clam when he's running around doing experiments and finding things out. He makes science fun for everyone in the lab."
Stecklein says that he plans to specialize in radiation oncology, with a focus on breast and gynecologic cancers. He completed his Ph.D. in pathology in May, and for now, his research career is taking a backseat to his medical education. He is currently on a pediatrics rotation, and will finish his medical degree in 2014.
A troublesome chaperone
Stecklein got the idea for his project after reading a study suggesting that a certain type of "heat shock protein" interacts with BRCA1. Cancer researchers are interested in heat shock proteins because they protect cancer cells when the cells are exposed to lethal conditions, such as those created by chemotherapy or radiation.
As it happens, a number of investigators at KU Medical Center are interested in Hsp90, the heat shock protein linked to BRCA1 in the 2003 study Stecklein read. With their help, he designed tests in an effort to formalize the nature of Hsp90's relationship with BRCA1.
The tests determined that Hsp90 serves as a sort of chaperone for BRCA1, giving it stability and regulating its ability to recognize and respond to DNA damage.
Given that BRCA1 helps tumors resist chemotherapy, disabling its chaperone seems like a sensible strategy for improving current treatments.
Turns out, there's a drug for that. The drug, tanespimycin, is a derivative of an antibiotic. It is currently in Phase II and III clinical evaluation for several cancers. The drug intrigues cancer researchers because of its ability to attach itself to and inhibit Hsp90.
The KU study suggests that tanespimycin or other new generation clinical Hsp90 inhibitors might work well with platinum-based chemotherapy drugs that cancer doctors currently use. By degrading the levels of BRCA1 — "You want to knock BRCA1 down," Stecklein says — these agents would essentially make tumors more vulnerable.
This treatment approach may make the most difference to women with non-hereditary ovarian cancer, who are more likely to receive platinum-based chemotherapy agents than breast cancer patients.
Patients with mutations in their BRCA genes may benefit, as well. Tumors that have BRCA1 abnormalities are often sensitive to platinum compounds, Jensen says. But as treatment continues, the tumors develop resistance through a BRCA1-mediated mechanism.
Jensen says the KU study points a way to disable the mechanism, which may lead to better outcome for cancer patients. "By circumventing it, we turn the tumor back into being susceptible to the original compound they were being treated with," he says.
Other KU authors of the study are Easwari Kumaraswamy, Ph.D., research assistant professor of pathology and laboratory medicine; Fariba Behbod, Pharm.D., Ph.D., assistant professor of pathology and laboratory medicine; Wenjia Wang, M.D., Ph.D., a former M.D./Ph.D. student in the Jensen lab; former research assistant Vamsee Chaguturu; and Lisa Harlan-Williams, Ph.D., research assistant professor of anatomy and cell biology.