Embargoed until after 12:01 a.m. Sunday, Oct. 22Studies at UNC-CH plumb tumor resistance to treatmentBy LESLIE H. LANGUNC-CH School of Medicine
(Embargoed) CHAPEL HILL - Cancer tumors with cells low in oxygen often survive and continue to grow despite the treatments thrown at them.
A scientist at the University of North Carolina at Chapel Hill has developed a method of identifying these hypoxic tumors. The method may lead to a greater understanding of treatment resistance, and help doctors more effectively predict the outcome of cancer therapies.
"For many years it's been known that cancerous tumors that have low amounts of oxygen are relatively resistant to the effects of radiation treatment," said Dr. Mahesh Varia, professor of radiation oncology at UNC-CH and a member of UNC Lineberger Comprehensive Cancer Center.
"More recently, we have learned that some hypoxic tumors are resistant to chemotherapy, and that patients with hypoxic tumors who are treated surgically do less well than patients with normally oxygenated tumors."
Currently, there is only one clinically advanced method that identifies tumor hypoxia at the cellular level. Moreover, it is highly accurate and does not require probing the tumor directly during an invasive procedure. This is the pimonidazole hypoxia marker invented by UNC-CH scientist Dr. James A. Raleigh, professor of radiation oncology and a member of the Lineberger center.
"When we started at UNC in 1988, our idea was to measure the amount of hypoxia in human tumors to predict which patients would do poorly after radiation, so this began as a predictive assay," he said. "We spent a number of years proving it in the laboratory and with animals in a veterinary setting and found it was feasible and low-tech."
The U.S. Food and Drug Administration has given the go-ahead to test as a diagnostic tool the pimonidazole hypoxia marker in human tumors.
In the test, the chemical pimonidazole is injected into the patient. As it circulates throughout the body, it binds only to cells with low oxygen concentrations. The tumor is then biopsied, usually the next day. Using special antibodies to pimonidazole that Raleigh developed and patented, tumor cells bound to the chemical can be detected by a laboratory immunoassay. Essentially, the test identifies the antibodies, which serve as markers for hypoxic cells.
On Oct. 23, at the annual meeting of the American Society for Therapeutic Radiology and Oncology, Varia will present UNC-CH research highlighting the value of the pimonidazole marker for studying the role hypoxia plays in tumor physiology. This includes how hypoxia combines with other factors to make tumors more aggressive and resistance to treatment.
Among other factors studied were cell proliferation, growth of new blood vessels (called angiogenesis) and gene expression of metallothionein (MT), an oxygen-regulated cellular protein that protects against chemotherapy and radiation. Because it's based on biopsied tissue, Raleigh's pimonidazole method for detecting hypoxia also allows scientists to focus on these and other factors in the same micro-regional tumor anatomy.
"Our interest in tumor hypoxia is twofold: One, if these tumors don't do as well with radiation, chemotherapy or surgery, then it's important that we assess that before we embark on treatment," Varia said. "The other important interest is in finding out why these hypoxic tumors are behaving badly? That's the thrust of this particular presentation."
Tumors from 36 patients were studied: 20 patients had cancers of the cervix and head and neck, 16 had breast cancer. Three or four random biopsy samples were obtained from each tumor and tested for hypoxia and other factors in aggressiveness and treatment resistance.
"So we looked at our biopsy samples, looked at hypoxia and looked at markers of cell proliferation, and we did not see a correlation," Varia said. Nor was there an association between tumor hypoxia and angiogenesis.
Varia, Raleigh and their collaborators now are looking for links between hypoxia and other factors, including gene expression of the protein MT.
In terms of that protein, Raleigh pointed out that in more than two-thirds of the tumor samples, MT was expressed in proliferating cells, but not in hypoxic cells. This was unexpected because in test tube studies of tumor cells exposed to hypoxia, metallothionein production is induced.
"So there's something about human tumors which changes the way gene expression operates, and it's different from what we see in test tubes and in mouse tumors, Raleigh noted." He and his colleagues will investigate this further.
"What we're demonstrating here is that the pimonidazole marker is a valuable approach to studying the mechanisms of hypoxia-associated poor prognosis," Varia said.
"We're also very interested in the translational aspect, taking findings from the laboratory into the clinic. And we appreciate our patients' participation in this type of research that advances our understanding of cancer and provides leads for better cancer treatment."
According to Raleigh, tumors from more than 200 patients around the world are being tested for hypoxia using his method. Beyond cancer treatment planning, clinical investigators at UNC-CH and elsewhere are looking at the hypoxia marker for studying alcohol-associated liver damage, wound healing and liver transplant success.
"It's a very novel tool that can be applied not only in cancer research but widely in medical investigations," Raleigh noted.
Funding for this research comes from the U.S. Department of Defense and the National Institutes of Health.
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Note to media: Dr. Mahesh Varia can be reached at (919) 966-7700 or [email protected]. From Oct. 23 to Oct. 25, Dr. Varia can be reached in Boston at (617) 954-3616. Dr. James Raleigh can be reached at (919) 966-7710 or [email protected]
UNC-CH School of Medicine contact: Les Lang, (919) 843-9687 or [email protected]
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