On March 7, 2022 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported that a manuscript has been published in the peer-reviewed journal Gastroenterology, authored by Curis collaborators at Washington University School of Medicine in St. Louis, on the role of IRAK4 in pancreatic ductal adenocarcinoma (PDAC) and the preclinical efficacy of emavusertib (CA-4948), a novel, small molecule IRAK4 inhibitor, in combination with checkpoint immunotherapy (Press release, Curis, MAR 7, 2022, View Source [SID1234609586]).
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"Through our emavusertib clinical trials, we have seen the potential of targeting IRAK4 in indications like non-Hodgkin’s lymphoma, acute myeloid leukemia and myelodysplastic syndromes," said James Dentzer, President and Chief Executive Officer of Curis. "Given the early, but compelling preclinical data outlined in Gastroenterology, IRAK4 targeting may have a broader application in treating solid tumors such as pancreatic cancer. We are thrilled to continue to identify new opportunities to potentially expand the development of emavusertib into additional cancer types as we work towards our goal of delivering novel, innovative cancer therapeutics in areas with significant unmet patient need."
The manuscript titled "IRAK4 signaling drives resistance to checkpoint immunotherapy in pancreatic ductal adenocarcinoma" concluded that tumor IRAK4 drives T-cell exhaustion in PDAC and is a promising therapeutic target when combined with checkpoint immunotherapy. Specifically, the experiments demonstrated that IRAK4 controls the NF-kB pathway and production of multiple checkpoint ligands, suppressive chemokines/cytokines, as well as hyaluronan synthase 2, all of which suppress T cell immune function against cancer. The study demonstrated that in a genetic mouse model that develops highly aggressive pancreatic cancer, IRAK4 can be targeted to overcome the immunosuppressive tumor microenvironment and drive response to checkpoint immunotherapy and validate the study of CA-4948 as a means to improve immunotherapeutic response in pancreatic cancer. The study team further confirmed this finding by generating a genetic mouse model in which the IRAK4 gene is deleted from the pancreatic cancer, providing firm evidence that IRAK4 is a promising therapeutic target in this deadly disease.
"Historically, the tumor microenvironment’s strong defense mechanisms have made cancers such as PDAC nearly impossible to treat effectively. Checkpoint immunotherapies, which have had a groundbreaking impact on other areas of oncology, are largely ineffective in PDAC," said Dr. Kian-Huat Lim, MD, PhD, Associate Professor of Medicine at Washington University School of Medicine, and Director of the GI Oncology Program. "Given the role of IRAK4 in NF-kB activation, we sought to explore whether there could be a translational benefit to targeting IRAK4 in PDAC. The results of our preclinical study show the promising effects of targeting IRAK4 in combination with chemotherapy and checkpoint immunotherapy, highlighting the potential of emavusertib to deliver effective therapeutic options to pancreatic cancer patients, who continue to have very limited therapeutic options."
The manuscript is available online at View Source(22)00201-3/pdf.
About Emavusertib (CA-4948)
Emavusertib is an IRAK4 kinase inhibitor and IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with AML and MDS. Third parties have recently discovered that the long form of IRAK4 (IRAK4-L) is oncogenic and preferentially expressed in over half of patients with AML and MDS. The overexpression of IRAK4-L is believed to be driven by a variety of factors, including specific spliceosome mutations such as SF3B1 and U2AF1.