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UVM, NYU Explore Role of ERK5 in Mesothelioma Progression, Treatment

Researchers at the College of Medicine at the University of Vermont and Langone Medical Center at New York University have concluded a study on the role of extracellular signaling regulated kinase 5 (ERK5) in mesothelioma pathogenesis. The team is now the first research collaborative to demonstrate that ERK5 plays a significant role in mesothelioma tumorigenesis and projected it as a potential therapeutic target.

In the study, the team used ERK5 silenced human mesothelioma cells, which exhibited significantly reduced tumor growth in immunocompromised mice. To advance the study, researchers tested a specific ERK5 inhibitor known as XMD8-92. The results showed:

  • XMD8-92 was significantly effective in killing mesothelioma cells grown as a 3-D spheroid model.
  • In H2373 cells (human mesothelioma cell line, fibrosarcomatoid), combining doxorubicin (chemotherapy) and XMD8-92 lead to a greater decrease in cell growth.
  • XMD8-92 has inhibitory effect on tumor growth in pleural as well as peritoneal models.
  • Levels of pro-inflammatory (IL-6) and angiogenic (VEGF) cytokine levels were significantly reduced in PLF (peritoneal lavage fluid) of XMD8-92 treated mice as compared to saline or vehicle treated mice. Note that inflammation fuels mesothelioma tumor growth.
  • XMD8-92 pretreated cells formed very few and small colonies as compared to vehicle treated cells (control).

In conclusion, the team wrote:

“Our studies here show that the ERK5 inhibitor, XMD8-92 can play a significant role in reducing mesothelioma tumor growth in pleural as well as peritoneal models and the mechanism may involve inflammasome inactivation. Results were encouraging in both immune-compromised as well as immune-competent mouse models. ERK5 inhibition via small molecule inhibitors in combination with chemotherapeutic drugs may be the future strategy to target mesotheliomas. A very recent report published by Lin et al. suggests that the effects observed by ERK5 inhibitors could in fact be off target effects. Keeping this in mind, new more specific inhibitors need to be tried as soon as they become commercially available” 

Though further studies are required to understand how ERK5 can regulate inflammasome transcription and/or activation, the team said, “our findings may lead the way to designing a more effective combination therapy for mesothelioma treatment.”

If you have been diagnosed with mesothelioma, talk to your doctor about innovative treatment protocols such as XMD8-92. Clinical trials for newer and developing treatments are often ongoing at cancer treatment centers around the globe. Talk to your doctor today.

 

Sources

Barrett, Trisha F., Harvey I. Pass, Jedd M. Hillegass, et al. "An Extracellular Signal–Regulated Kinase 2 Survival Pathway Mediates Resistance of Human Mesothelioma Cells to Asbestos-Induced Injury." ATS Journals. American Thoracic Society, 2011. Web. 18 Mar. 2018.

Thompson, Joyce K., Anurag Shukla, Alan L. Leggett, et al. "Extracellular Signal Regulated Kinase 5 and Inflammasome in Progression of Mesothelioma." Oncotarget. Impact Journals LLC, 02 Jan. 2018. Web. 18 Mar. 2018.