SBIR-STTR Award

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.

Public Health Relevance Statement:


Public Health Relevance:
GlycoMira seeks to develop a simple, mechanistically-based treatment for oral mucositis, a common and debilitating complication of cancer treatment. Cancer patients undergoing radiation or chemotherapy develop painful, severe ulcerations of the mouth that severely impair the patient's quality of life and compromise treatment and prognosis because their presence causes the physician to reduce the doses of chemotherapy or radiation.

Project Terms:
Antiinflammatory Agents; Antiinflammatories; Anti-Inflammatories; Anti-Inflammatory Agents; Blood Reticuloendothelial System; Blood; necrocytosis; Cell Death; Cells; clinical investigation; Clinical Trials; Infectious Disorder; Infectious Diseases and Manifestations; Infectious Diseases; Infectious Disease Pathway; Communicable Diseases; Complication; Swallowing; Deglutition; disease/disorder; Disorder; Disease; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Epithelial Cells; Feasibility Studies; digestive canal; alimentary tract; Gastrointestinal Tract; GI Tract; Digestive Tract; Alimentary Canal; Gastrointestinal tract structure; Mucopolysaccharides; Glycosaminoglycans; Hospitalization; In Vitro; Incidence; Inflammation; heavy metal lead; heavy metal Pb; Pb element; Lead; macrophage; oral mucosal; oral mucosae; Oral Mucosa; Mouth Mucosa; Buccal Mucosa; Oral mucous membrane structure; Murine; Mice Mammals; Mice; Mus; Necrotic; Necrosis; Polymorphonuclear Neutrophils; Polymorphonuclear Leukocytes; Polymorphonuclear Cell; Polymorph; Neutrophilic Leukocyte; Neutrophilic Granulocyte; Marrow Neutrophil; Heterophil Granulocyte; Blood Segmented Neutrophil; Blood Polymorphonuclear Neutrophil; Blood Neutrophil; neutrophil; Opportunistic Infections; Painful; Pain; Patients; Myeloperoxidase; Hemi-Myeloperoxidase; Peroxidases; Physicians; Prognosis; outcome forecast; QOL; Quality of life; Radiation Dosage; Radiation-Ionizing Total; Ionizing Electromagnetic Radiation; Ionizing radiation; Radiotherapy; Radiotherapeutics; Radiation therapy; Research; Acne Rosacea; Rosacea; biological signal transduction; Signaling; Signal Transduction Systems; Intracellular Communication and Signaling; Cell Signaling; Cell Communication and Signaling; Signal Transduction; Technology; Testing; Body Tissues; Tissues; tube feeding; Ulceration; Ulcer; Work; dry mouth; aptyalism; Mouth Dryness; Hyposalivation; Asialia; Xerostomia; palifermin; SDGF-3; Fibroblast Growth Factor 7; FGF-7; keratinocyte growth factor; cytokine; Measures; health care; Healthcare; Mediating; TQ1 Antigen; Mel-14 Antigen; Lymphocyte Adhesion Molecule 1; Leu-8 Antigen; LECAM-1; LAM-1 Leukocyte Adhesion Molecule; LAM-1; CD62L Antigens; L-Selectin; base; dosage; Area; Clinical; Mouth; Cavitas Oris; Buccal Cavity Head and Neck; Buccal Cavity; Oral cavity; insight; malignant head and neck tumor; Malignant Head and Neck Neoplasm; Head and Neck Cancer; painful bladder syndrome; bladder pain syndrome; Interstitial Cystitis; Blocking Antibodies; Therapeutic; Attenuated; Staging; Inflammatory; Mucosal Inflammation; Mucositis; radiochemotherapy; radio-chemotherapy; chemoradiotherapy; chemo-radiotherapy; chemoradiation; Severities; Oral; Salivary; microorganism; Visit; Emergency room; Emergency Department; Accident and Emergency department; cell damage; Cellular injury; cell injury; model organism; Animal Models and Related Studies; Animal Model; experimental study; experimental research; experiment; research study; topically applied; topical drug application; topical administration; Topical Drug Administration; Topical application; Reporting; Toll/Interleukin 1 Receptor-Like Protein 4; Toll/Interleukin 1 Receptor-Like 4; TLR2 receptor; Toll-Like Receptor 2; ray (radiation); Radiation; response; anticancer therapy; Malignant Neoplasm Treatment; Malignant Neoplasm Therapy; Cancer Treatment; cancer therapy; Sequence-Specific Posttranscriptional Gene Silencing; RNAi; RNA Silencing; Quelling; Posttranscriptional Gene Silencing; Post-Transcriptional Gene Silencing; RNA Interference; irradiation; preventing; prevent; Dose; Symptoms; Data; Interruption; in vivo; in vivo Model; Anti-inflammatory; Apoptotic; Cancer Patient; Signaling Molecule; Molecular; Process; Therapeutic Effect; developmental; Development; oromucositis; oral mucositis; pathway; Pathway interactions; cost; chemotherapy; mouse model; novel therapeutic target; new therapeutic target; public health relevance; FDA approved; molecular marker; Regimen

Oral mucositis is a devastatingly painful inflammatory disease that frequently develops during cancer therapy and affects half a million people in the US. The accompanying pain is so severe that patients often require narcotic pain medicines. The clinical manifestations are ulcers in the mouth and gastrointestinal tract, which are exacerbated by opportunistic infections. Many patients also suffer from dry mouth causing difficulty in swallowing because of the decreased salivary gland function. As a result, these patients often need feeding tubes which interrupts their cancer treatment. The financial burden to the patient is staggeringly high costing an additional $17,000 to $40,000 for each patient. Preventing oral mucositis will therefore greatly enhance the cancer therapy as well as the wellness of the patients. GlycoMira's lead candidate, GM-0111, is a new class of anti-inflammatory drugs. The SBIR Phase I study results demonstrate its powerful anti-inflammatory effects in a radiation-induced oral mucositis animal model: GM-0111 reduced tissue ulceration and inflammation in the tongue. Histologically, tongue tissues from the GM-0111 treated group showed markedly reduced infiltration of leukocytes with thicker mucosal layers and prevention of mucous glandular alterations compared to the tissues from vehicle treated animals. Biochemical analyses also showed consistently lower leukocyte enzyme MPO activity as well as reduced concentration of nerve growth factor (NGF) in GM-0111 treatment groups. In addition, GM-0111 treatment prevented radiation-induced alterations of the salivary glands. Overall, the data suggest that it is feasible to use GM-0111 to prevent oral mucositis. The current SBIR Phase II application proposes to further develop GM-0111 as a viable and effective therapy for oral mucositis. The objectives are to (1) investigate the optimal dosing regimen in a radiation-induced oral mucositis animal model, (2) determine the optimal formulation for topical delivery of GM-0111 in the oral mucosa, (3) validate the topical GM-0111 formulation in radiation and chemoradiation-induced animal models, and (4) investigate the molecular targets of GM-0111 to reduce oral mucositis. The results of the proposed research will lead to the delivery of a viable and effective therapy to the patients suffering from this devastating disease.

Public Health Relevance Statement:
PROJECT NARRATIVE GlycoMira seeks to develop a simple, mechanistically-based treatment for oral mucositis, a common and debilitating complication of cancer treatment. Cancer patients undergoing radiation therapy develop painful, severe ulcerations of the mouth that seriously degrade the patient's quality of life and compromise treatment and prognosis because their presence causes the physician to interrupt the course of cancer therapy.

Project Terms:
Affect; Animals; Antiinflammatory Agents; Antiinflammatories; Anti-Inflammatories; Anti-Inflammatory Agents; Cathepsins; necrocytosis; Cell Death; Cell Body; Cells; Complication; Swallowing; Deglutition; Disorder; Disease; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Enzyme Gene; Enzymes; Epithelial Cells; Feasibility Studies; digestive canal; alimentary tract; Gastrointestinal Tract; GI Tract; Digestive Tract; Alimentary Canal; Gastrointestinal tract structure; Mucopolysaccharides; Glycosaminoglycans; Hamsters Mammals; Cricetinae; Hamsters; Modern Man; Human; allergic/immunologic organ system; allergic/immunologic body system; Immune system; Inflammation; heavy metal lead; heavy metal Pb; Pb element; Lead; white blood corpuscle; white blood cell; White Cell; White Blood Cells; Marrow leukocyte; Leukocytes Reticuloendothelial System; Blood leukocyte; Leukocytes; Medicine; oral mucosal; oral mucosae; Oral Mucosa; Mouth Mucosa; Buccal Mucosa; Oral mucous membrane structure; mucous; Mucus; Mucous body substance; Murine; Mice Mammals; Mice; Mus; Narcotics; Necrotic; Necrosis; Neurotrophic Proteins; Neuronotrophic Factors; Nerve Growth Factors; Opportunistic Infections; Painful; Pain; Patients; Phagocytosis; Physicians; Prognosis; outcome forecast; QOL; Quality of life; treatment with radiation; radio-therapy; radiation treatment; Radiotherapy; Radiotherapeutics; Radiation therapy; Research; Safety; Salivary Glands Head and Neck; Salivary Glands; Signal Pathway; biological signal transduction; Signaling; Signal Transduction Systems; Intracellular Communication and Signaling; Cell Signaling; Cell Communication and Signaling; Signal Transduction; Testing; Time; Body Tissues; Tissues; Tongue; transplant; Transplantation; Ulcer; Ulceration; Xerostomia; dry mouth; aptyalism; Mouth Dryness; Hyposalivation; Asialia; Measures; Enteral Feeding; tube feeding; gastric feeding; feeding tube; enteric feeding; Mediating; Schedule; base; Acute; Clinical; repair; repaired; Phase; Histologically; Histologic; Biochemical; Mouth; Cavitas Oris; Buccal Cavity Head and Neck; Buccal Cavity; Oral cavity; insight; malignant head and neck tumor; Malignant Head and Neck Neoplasm; Head and Neck Cancer; Blocking Antibodies; Staging; Infiltration; Inflammatory; Mucosal Inflammation; Mucositis; Malignant Cell; cancer cell; radiochemotherapy; radio-chemotherapy; radio-chemo-therapy; chemoradiotherapy; chemo-radiotherapy; chemo-radio-therapy; chemo-/radio-therapy; chemoradiation; Frequencies; Complex; Event; Oral; Tumor Cell; neoplastic cell; cell damage; Cellular injury; cell injury; model organism; Animal Models and Related Studies; Animal Model; experimental study; experimental research; experiment; research study; topically applied; topical drug application; topical delivery; topical administration; Topical Drug Administration; Topical application; Prevention; Radiation; Modeling; anticancer therapy; Malignant Neoplasm Treatment; Malignant Neoplasm Therapy; Cancer Treatment; cancer therapy; Cytoprotective Drugs; Cytoprotectants; Cytoprotective Agent; Thickness; Thick; irradiation; preventing; prevent; Toll/Interleukin 1 Receptor-Like Protein 4; Toll/Interleukin 1 Receptor-Like 4 Gene; Toll/Interleukin 1 Receptor-Like 4; Toll-Like Receptor 2; TLR2 receptor; TLR2; TIL4; TLR2 gene; toll-like receptor 4; Toll Homologue; TLR4; Homolog of Drosophila TOLL; TLR4 gene; Dose; Data; Molecular Target; Anti-inflammatory; Apoptotic; Cancer Patient; Cell Death Signaling; Cell Death Signaling Process; Signaling Molecule; Small Business Innovation Research; SBIR; Small Business Innovation Research Grant; Molecular; Process; developmental; Development; oromucositis; oral mucositis; pathway; Pathway interactions; cost; protective effect; tumor; FDA approved; effective therapy; effective treatment; phase 1 study; Phase I Study; Regimen; cytotoxic radiation; treatment group; Formulation