Aclaris Therapeutics publishes zunsemetinib preclinical research

By Andre Rickard, The Science Advisory Board contributing writer

December 6, 2021 -- Aclaris Therapeutics has published preclinical research of zunsemetinib in pancreatic cancer in Science Translational Medicine on December 1.

The article presents the results from a preclinical study using patient-derived cell lines and an autochthonous pancreatic ductal adenocarcinoma mouse model that evaluated the role of MAPK activated protein kinase 2 (MK2) and the impact of zunsemetinib, Aclaris' investigational oral small molecule MK2 inhibitor, in pancreatic cancer.

The study was a multiyear collaboration between Aclaris and the Washington University School of Medicine, led by Drs. Kian-Huat Lim, PhD, and Patrick Grierson, PhD, both of whom are assistant professors in the oncology division at Washington University School of Medicine in St. Louis.

In the study, Lim and his team identified the MK2/heat shock protein 27 (HSP27) axis as an important resistance mechanism, resulting in pancreatic tumor cell survival following exposure to components of Folfirinox chemotherapy -- the current standard treatment for pancreatic cancer.

Lim's team also demonstrated that DNA damage induced by Folfirinox chemotherapy components upregulated tumor necrosis factor alpha (TNFa) in pancreatic cancer cells, which had the dual effect of impacting cell death and cell survival. Moreover, the selective inhibition of MK2 downstream of TNFa signaling abrogated survival through blocking HSP27 activation and beclin1-mediated autophagy, which allowed TNFa to execute its prodeath mechanism. The researchers then showed that mouse survival in a model of pancreatic cancer was statistically significantly extended when dosed with zunsemetinib in combination with Firinox (a murine version of Folfirinox).

Based on these results and clinical data generated from Aclaris' clinical development program with zunsemetinib, Aclaris is considering a future clinical program for the treatment of patients with pancreatic cancer using one of Aclaris' other MK2 inhibitor drug candidates.

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