Clinically relevant model mice for difficult to treat cancer of the lung squamous cell -
Only 15% of patients with lung squamous cell cancer - the second cancer the most common lung - survive five years past diagnosis. Little is understood about how the deadly disease arises, preventing the development of targeted therapies that could serve as a second line of defense after standard chemotherapy fails.
Published online cell reports June 19, the Huntsman Cancer Institute investigators indicate that misregulation of two genes, sox2 and LKB1, causes squamous cell lung cancer in mice. The discovery discover new treatment strategies, and provides a clinically relevant mouse model in which to test them.
"This is the most exciting thing we've done," said lead author Trudy Oliver, Ph.D., an assistant professor of oncology at the University of Utah and Huntsman cancer Institute investigator. "Now that we have a model, it unleashed so many questions we can ask to get a better understanding of the disease."
By definition, tumors are groups of cells that are out of control. For therefore, they acquire mutations, only certain properties that result - such as growth and excess mobility. - that make cancer cells the trick for the development of targeted therapies is to distinguish the "driver" mutations "passengers" who are just along for the ride.
Call it guilt by association, but Oliver polished team in squamous carcinoma of drivers (SCC) of the lung by poring through documented genetic abnormalities found in human SCC. Sox2 was designated candidate of choice based on its overexpression in 60-0% of SCC and early onset frequent during the formation of the tumor, suggesting that it could be a cancer initiator. the tumor suppressor genes are also candidates, including LKB1 that is mutated in 5 to 19% of CSC.
Although the disruption of either gene alone failed to trigger cancer, Sox2 overexpression in lung combination with a loss of LKB1 leads to frequent development of CSC lung in mice.
"A pathologist looking under the microscope in our tumors would not know that it is the mouse," said Oliver. "They look like visually human tumors, and then when we staining of biomarkers of human disease, our mouse tumors light up to these markers."
Unlike CSC models most previously existing mouse lung that develop multiple tumor types, the model sox2 / LKB1 generates CSC exclusively. Combine that with the fact that it was created on the basis of patient data makes clinically relevant model, and well prepared for testing new targeted therapies.
"In addition to lung cancer, the model results may have important clinical implications for other malignancies or squamous led Sox2 such as cancer of the small cell lung, and brain, esophagus, and cancers of the mouth, "said Anandaroop Mukhopadhyay, Ph.D., Huntsman cancer Institute investigator and senior author on the paper.
Although there are no known drugs that directly target either Sox2 or LKB1, there are existing therapies that interfere with the biochemical pathways that are thought to be activated by these genes. In addition, the scientists found that these pathways, Jak-Stat and mTOR, were activated in tumors in the new model of the mouse. These findings suggest that drugs that block these pathways, inhibitors of mTOR and STAT3, are good candidates to work as lung SCC targeted therapies.
"These are ways that has not been previously explored for the treatment of squamous tumors because we did not know they were important," said Oliver. "This gives us the direction to test the effectiveness of drugs to these channels. "
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