Posted November 13, 2014
Trudy Oliver, Ph.D., from the University of Utah, is a recipient of a Fiscal Year 2011 Lung Cancer Research Program Concept Award.
1. What is the most important thing that stakeholders should know about your research?
We have created a novel mouse model of squamous cell lung cancer. This model serves as a critical tool to understand how this disease arises and to identify novel treatment strategies. Squamous cell lung cancer is the second most common type of lung cancer, responsible for ~40,000 deaths each year in the United States alone. Unlike other types of lung cancer, there are no targeted therapies approved for treatment. Because of its poor survival rate, there is an urgent need for model systems to better understand the genetic causes of this disease and how to treat it.
The model we created is based upon expression of a gene called Sox2, which is one of the most commonly altered genes in human squamous lung tumors. However, alterations in Sox2 alone do not cause squamous lung tumors. We discovered that activation of the mTOR pathway cooperates with Sox2 to promote squamous lung tumors. Our work demonstrates that mouse tumors are remarkably similar to the human disease on many levels. Importantly, small molecular inhibitors of the mTOR pathway exist and may be useful for the treatment of squamous lung tumors. In addition, we discovered that the JAK/STAT pathway is activated in Sox2-driven tumors, suggesting that small molecule inhibitors against this pathway may also represent a potential new drug target.
2. How did you arrive at this information or approach?
Our goal was to create a model of squamous cell lung cancer based on the known alterations in the human disease. In 2012, The Cancer Genome Atlas sequenced human squamous lung tumors and identified numerous gene alterations that could be driving the disease. We used a creative strategy to alter combinations of two genes simultaneously in the mouse lungs using lentiviruses as a gene delivery tool. One combination of genes (overexpression of Sox2 and loss of Lkb1) led to squamous lung tumors in the mice. These tumors highly resembled the human disease on many levels, in their appearance, gene expression, and activation of potentially druggable pathways.
3. What is the next step to bringing your research closer to helping lung cancer patients?
Our model suggests that certain signaling pathways are activated in both mouse and human squamous lung tumors, including the mTOR and JAK/STAT pathways. This suggests these pathways may serve as new drug targets for squamous cell lung cancer. Our current efforts are aimed at testing whether inhibition of these pathways in the mouse model, alone and in combination with chemotherapy, can successfully treat squamous lung tumors. If these studies are successful, the next step will be to translate these findings to clinical trials.
Mukhopadhyay A, Berrett KC, Kc U, Clair PM, Pop SM, Carr SR, Witt BL, Oliver TG. 2014. Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer. Cell Reports Jul 10;8(1):40-49.
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