BUFFALO, N.Y., May 1, 2013 (GLOBE NEWSWIRE) -- Cleveland BioLabs, Inc. (Nasdaq:CBLI) and Roswell Park Cancer Institute (RPCI) today announced the publication of studies identifying the liver as a key mediator of Entolimod's tissue-protective and anticancer activities in Proceedings of the National Academy of Sciences of the United States of America ( PNAS), the official journal of the United States National Academy of Sciences. The reported studies were conducted by scientists at Roswell Park Cancer Institute and Cleveland BioLabs (CBLI) in collaboration with researchers at Attagene, Inc. and the Gamaleya Research Institute for Epidemiology and Microbiology in Moscow.
Entolimod is a Toll-like receptor 5 (TLR5) agonist currently under development by CBLI as both a radiation countermeasure and a cancer agent. Previous work showed that the biological effects of Entolimod stem from TLR5-mediated activation of NF-kB, a transcriptional regulator that induces multiple genes encoding tissue-protective factors, such as inhibitors of programmed cell death, scavengers of reactive oxygen species, and cytokines that promote cell proliferation and differentiation. The current studies were aimed at defining the mechanism of systemic response to Entolimod at the molecular and cellular levels. The results showed that the liver is a major primary target organ of Entolimod. The specific responsiveness of one particular type of liver cell, the hepatocyte, distinguishes TLR5 from other TLRs and provides plausible explanation for superior pharmacological properties of Entolimod compared to agonists of other TLRs.
A novel technique called Factorial™, developed by Attagene, was utilized to define molecular signaling pathways modulated by Entolimod in the liver. This technique made it possible to simultaneously monitor the activity of close to 50 inducible transcription factors in the liver of treated animals. In addition to the NF-kB pathway, Entolimod treatment was found to activate several other pro-survival and immunoregulatory signaling pathways in hepatocytes, culminating in induction of secreted cytokines and recruitment of immune cells to the liver. In several animal models tested, this led to suppression of tumor cell growth in the liver regardless of whether the tumor cells expressed TLR5. These results expand the potential anticancer applications of Entolimod beyond treatment of TLR5-expressing primary tumors to include prevention and/or treatment of metastases to the liver, irrespective of the primary tumor's TLR5 status. The liver is among the most common metastatic sites for several different types of cancer. Of particular importance, while Entolimod treatment induced changes in the liver microenvironment that counteracted tumor cell growth, it also made normal liver cells resistant to a form of cell death commonly involved in hepatotoxicity. This finding suggests that Entolimod may offer a new approach for liver protection in a variety of clinical scenarios.
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