CLEVELAND, Ohio—Two very painful and difficult-to-treat inflammatory diseases—Crohn's Disease and sarcoidosis—may have new avenues for treatment, thanks to a study recently published by researchers at the Case Western Reserve University School of Medicine.
The study, published Dec. 1 in the Cold Spring Harbor Press journal Genes & Development, suggests that two cancer drugs already on the market—Roche's Tarceva and AstraZeneca's Iressa—could hold promise for patients with these diseases because they may benefit conditions exacerbated by NOD2 hyperactivation.
For the last decade, Case Western assistant professor of pathology Dr. Derek Abbott has been working to discover how the NOD2 gene, which is linked to inflammatory diseases such as inflammatory bowel disease, Crohn's Disease and Blau syndrome, affects not just Crohn's, but the immune system in general. While the loss of NOD2, the gene studied in Abbott's study, increases the risk of developing Crohn's disease, increased activity of this gene is also thought to exacerbate symptoms. Additionally, activating NOD2 mutations can cause genetic sarcoidosis, an inflammatory disease affecting multiple organs in the body, but primarily the lungs and lymphoid tissue.
"NOD2is a funny protein," Abbott, who served as lead author on the study, explains. "Inside the cell, it gets activated when a bacterial product meets it. So a bacteria has to be taken up by the cell and broken down, or has to invade the cell to cause intracellular infection. When activated, it binds to a protein kinase called RIP2. It's designed to set up a cytokine response. There has to be a very tight balance to not only turn on the signaling pathway to get rid of the pathogen, but also to turn it off, or you will end up with inflammatory disease."
Although NOD2 itself has no enzymatic activity, because RIP2 is a kinase, it has become one of the most successful drug targets in the last 10 years, particularly for the treatment of both solid and blood-based cancers. Abbott and his team set out to screen known tyronsine kinase inhibitors and found that Tarceva and Iressa, which target the cancer cells' epidermal growth factor receptor (EGFR) protein kinase to inhibit the growth of both lung cancer and brain cancer, are very potent against RIP2.
Given this tyrosine kinase activity, Abbott's team performed small-molecule inhibitor screen designed to identify pharmacologic agents that inhibit RIP2's tyrosine kinase activity. At nanomolar concentrations, Tarceva and Iressa were found to inhibit both RIP2 tyrosine phosphorylation and muramyl dipeptide-induced cytokine release in a variety of NOD2 hyperactivation states. This effect is specific for RIP2 and does not depend on EGFR.
The finding that RIP2 has tyrosine kinase activity and that these FDA-approved drugs inhibit this activity suggests that RIP2's tyrosine kinase activity could be targeted specifically in the treatment of inflammatory diseases, Abbott says—though he cautions that researchers have yet to test this theory in animal models.
"We believe that in the future, this could be used as a marker of activation of the NOD2 pathway," he says. "It could also be used to screen patients to see if they have an overactive NOD2 pathway."
Those findings could also have implications for personalized medicine, says personal health expert Dr. Kathryn Teng, director of Clinical Integration of Personalized Healthcare at the Cleveland Clinic and assistant professor of medicine at Case Western.
"Like many cancer chemotherapeutics, Tarceva and Iressa cause side effects in cancer patients, including skin rash and diarrhea," Teng explains. "It would be interesting to determine if these side effects change as a function of a patient's NOD2 status and if the dosing needs to be adjusted in patients with mutant NOD2 versus those with normal NOD2. Although these results are very preliminary in terms of patient care, their implications for personalized medicine are intriguing and might give a wide variety of reasons to test for NOD2 mutation status in a broader subset of patients."
With an eye toward this future clinical development, Abbott's team is working with the university's Technology Transfer Office and pharmaceutical companies to further test the clinical potential of their findings. To Abbott's knowledge, neither Roche nor AstraZeneca were aware of the study prior to its publishing. The companies did not respond to a request for comment on this story.
"We need to move this on to in vivo models," Abbott says. "Of course, being an academic institution, we would love the drug companies to do this. We'd like to set up a model of sarcoidosis. The next obvious step, we believe, is to use these agents in an asthma model to see if we can inhibit the development of disease in mice."
The study, "Inhibition of RIP2's tyrosine kinase activity limits NOD2-driven cytokine responses," was funded in part by grants from the National Institutes of Health and the Burroughs Wellcome Foundation. Justine T. Tigno-Aranjuez, a colleague of Abbott's in Case Western's pathology department, and John M. Asara of the Division of Signal Transduction at Beth Israel Deaconess Medical Center in Boston, served as co-authors.
The study, published Dec. 1 in the Cold Spring Harbor Press journal Genes & Development, suggests that two cancer drugs already on the market—Roche's Tarceva and AstraZeneca's Iressa—could hold promise for patients with these diseases because they may benefit conditions exacerbated by NOD2 hyperactivation.
For the last decade, Case Western assistant professor of pathology Dr. Derek Abbott has been working to discover how the NOD2 gene, which is linked to inflammatory diseases such as inflammatory bowel disease, Crohn's Disease and Blau syndrome, affects not just Crohn's, but the immune system in general. While the loss of NOD2, the gene studied in Abbott's study, increases the risk of developing Crohn's disease, increased activity of this gene is also thought to exacerbate symptoms. Additionally, activating NOD2 mutations can cause genetic sarcoidosis, an inflammatory disease affecting multiple organs in the body, but primarily the lungs and lymphoid tissue.
"NOD2is a funny protein," Abbott, who served as lead author on the study, explains. "Inside the cell, it gets activated when a bacterial product meets it. So a bacteria has to be taken up by the cell and broken down, or has to invade the cell to cause intracellular infection. When activated, it binds to a protein kinase called RIP2. It's designed to set up a cytokine response. There has to be a very tight balance to not only turn on the signaling pathway to get rid of the pathogen, but also to turn it off, or you will end up with inflammatory disease."
Although NOD2 itself has no enzymatic activity, because RIP2 is a kinase, it has become one of the most successful drug targets in the last 10 years, particularly for the treatment of both solid and blood-based cancers. Abbott and his team set out to screen known tyronsine kinase inhibitors and found that Tarceva and Iressa, which target the cancer cells' epidermal growth factor receptor (EGFR) protein kinase to inhibit the growth of both lung cancer and brain cancer, are very potent against RIP2.
Given this tyrosine kinase activity, Abbott's team performed small-molecule inhibitor screen designed to identify pharmacologic agents that inhibit RIP2's tyrosine kinase activity. At nanomolar concentrations, Tarceva and Iressa were found to inhibit both RIP2 tyrosine phosphorylation and muramyl dipeptide-induced cytokine release in a variety of NOD2 hyperactivation states. This effect is specific for RIP2 and does not depend on EGFR.
The finding that RIP2 has tyrosine kinase activity and that these FDA-approved drugs inhibit this activity suggests that RIP2's tyrosine kinase activity could be targeted specifically in the treatment of inflammatory diseases, Abbott says—though he cautions that researchers have yet to test this theory in animal models.
"We believe that in the future, this could be used as a marker of activation of the NOD2 pathway," he says. "It could also be used to screen patients to see if they have an overactive NOD2 pathway."
Those findings could also have implications for personalized medicine, says personal health expert Dr. Kathryn Teng, director of Clinical Integration of Personalized Healthcare at the Cleveland Clinic and assistant professor of medicine at Case Western.
"Like many cancer chemotherapeutics, Tarceva and Iressa cause side effects in cancer patients, including skin rash and diarrhea," Teng explains. "It would be interesting to determine if these side effects change as a function of a patient's NOD2 status and if the dosing needs to be adjusted in patients with mutant NOD2 versus those with normal NOD2. Although these results are very preliminary in terms of patient care, their implications for personalized medicine are intriguing and might give a wide variety of reasons to test for NOD2 mutation status in a broader subset of patients."
With an eye toward this future clinical development, Abbott's team is working with the university's Technology Transfer Office and pharmaceutical companies to further test the clinical potential of their findings. To Abbott's knowledge, neither Roche nor AstraZeneca were aware of the study prior to its publishing. The companies did not respond to a request for comment on this story.
"We need to move this on to in vivo models," Abbott says. "Of course, being an academic institution, we would love the drug companies to do this. We'd like to set up a model of sarcoidosis. The next obvious step, we believe, is to use these agents in an asthma model to see if we can inhibit the development of disease in mice."
The study, "Inhibition of RIP2's tyrosine kinase activity limits NOD2-driven cytokine responses," was funded in part by grants from the National Institutes of Health and the Burroughs Wellcome Foundation. Justine T. Tigno-Aranjuez, a colleague of Abbott's in Case Western's pathology department, and John M. Asara of the Division of Signal Transduction at Beth Israel Deaconess Medical Center in Boston, served as co-authors.
