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.
Finally, by showing that occlusion of hepatic blood circulation eliminated Entolimod-mediated radioprotection of the hematopoietic system, the reported work strongly suggests that exposure of liver cells to Entolimod is essential for the drug's radioprotective and radiomitigating activity. Therefore, factors secreted by responsive hepatocytes appear to be responsible, at least in part, for the ability of Entolimod to protect and stimulate regeneration of the hematopoietic system in irradiated animals.
Andrei Gudkov, Ph.D., D.Sci., Chief Scientific Officer of Cleveland BioLabs, Senior Vice President of Basic Science at RPCI and corresponding author of the paper, commented: "Entolimod continues to pleasantly surprise us. The studies reported in this publication represent the first comprehensive work on TLR5 signaling conducted in vivo. They provide new mechanistic insight into the radioprotection, radiomitigation and anticancer activities of Entolimod, strengthening both our understanding of the drug's ability to mitigate radiation damage to the hematopoietic system and the hypothesis behind an ongoing clinical study with the drug in advanced cancer patients at Roswell Park Cancer Institute. Moreover, the previously unanticipated effects of Entolimod on hepatocytes and the liver microenvironment defined in this work suggest that prevention or treatment of liver metastases and protection of the liver from various types of cell stress are additional areas of prospective clinical application for Entolimod."
Jean Viallet, M.D., Chief Development Officer at Cleveland BioLabs, stated, "The intense liver-directed immune response induced by Entolimod resulted in the prevention of liver metastases in several experimental models. Several types of human cancer show a strong predilection to metastasize to the liver. The clinical implications are exciting, and our team is already developing clinical trials to bring these new concepts to patients."
The work reported in the publication was supported by National Institutes of Health Grants R01AI080446 and RC2AI087616 and by Cleveland BioLabs, Inc., as well as by the Defense Threat Reduction Agency of the U.S. Department of Defense under Contract HDTRA1-11-C-0008 (to Cleveland BioLabs, Inc.).
The PNAS publication can be found online at: http://www.pnas.org/content/early/2013/04/25/1222805110.abstract
About Cleveland BioLabs, Inc.
Cleveland BioLabs, Inc. is a clinical-stage biotechnology company leveraging deep mechanistic understanding of the cell death process, apoptosis, to develop a robust pipeline of compounds primarily focused on oncology applications and mitigation of radiation injury. The Company's lead compound is being developed as both a radiation countermeasure and a cancer treatment. The Company has two operating subsidiaries, Incuron, LLC, and Panacela Labs, Inc., and strategic relationships with the Cleveland Clinic, Roswell Park Cancer Institute, the Children's Cancer Institute Australia and the Armed Forces Radiobiology Research Institute. To learn more about Cleveland BioLabs, Inc., please visit the Company's website at http://www.cbiolabs.com.
About Roswell Park Cancer Institute:
The mission of Roswell Park Cancer Institute (RPCI) is to understand, prevent and cure cancer. RPCI, founded in 1898, was one of the first cancer centers in the country to be named a National Cancer Institute-designated comprehensive cancer center and remains the only facility with this designation in Upstate New York. The Institute is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation's leading cancer centers; maintains affiliate sites; and is a partner in national and international collaborative programs. For more information, visit RPCI's website at http://www.roswellpark.org, call 1-877-ASK-RPCI (1-877-275-7724) or email firstname.lastname@example.org.
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