Glycosaminoglycans to Treat and Prevent Radiation-Induced Oral Mucositis

Glycomira, Llc, Salt Lake City UT

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Abstract

DESCRIPTION (provided by applicant): GlycoMira Therapeutics has developed safe and effective anti-inflammatory glycosaminoglycan derivatives and proposes to test the feasibility of using its lead compound to treat or prevent oral mucositis. Mucositis is a common and debilitating complication of cancer treatment. Cancer patients undergoing radiation or chemotherapy often develop this painful inflammatory disease within a week of starting radio-chemotherapy. The clinical manifestations include ulcers in the mouth and gastrointestinal tract, and are exacerbated by opportunistic infections by oral and pathogenic microorganisms. Many patients also suffer from dry mouth due to decreased salivary flow, with pain and difficulty in swallowing, often necessitating installation of a feeding tube. The severity of mucositis frequently results in interruptions to the cancer treatment, dose reductions and even unplanned emergency room visits and hospitalizations. In head and neck cancer treatments, where more than 80% of the patients will develop this disorder, mucositis adds an average cost of $17,000 per patient, significantly increasing the financial burden on health care payers. Current treatments only serve to manage mucositis-related symptoms and pain; Palifermin, the only FDA approved therapeutic, shows marginal efficacy in reducing the incidence of radiation-induced mucositis. Experts cite failed clinical trials of many common anti-inflammatory drugs, highlighting the need for a new therapeutic that targets the initial stages of mucositis. On a molecular level, mucositis is initiated by the release of pro-inflammatory signaling molecules from cells damaged by radiation or chemotherapy treatment. These signaling molecules in turn attract inflammatory cells to the area and amplify apoptotic cell death in nearby healthy cells. While many key molecular factors involved in the early inflammatory process remain unclear, these early molecular factors are potential targets for developing an effective therapeutic for mucositis. GlycoMira's lead candidate GM-0111 prevents inflammation-induced cell death and blocks inflammatory pathways that include P- and L-selectins, myeloperoxidase from neutrophils, and RAGE activation in vitro. We hypothesize that GM-0111 prevents radiation-induced mucositis by inhibiting early inflammatory signaling. In this proposal, (1) we will study the feasibility of using GM-0111 to reduce radiation-induced oral mucositis in an in vivo model of the disease, and (2) we will elucidate the cytoprotective mechanism of GM-0111 in x-ray induced cell death. The results of this research will provide insight into the molecular mechanism important in the early stages of mucositis and the potential of GM-0111 in mitigating radiation-induced mucositis.