Oral ulcerative mucositis is a common, painful, dose-limiting toxicity of chemotherapy and radiation therapy for cancer, and represents an important unmet clinical need with 450,000 Americans suffering from mucositis each year. It impacts virtually all patients receiving concomitant chemoradiation therapy for tumors of the mouth and oropharynx. Aside from its devastating symptomatic impact, resulting in opiod-requiring pain and the need for gastrostomy feeding, mucositis is a major driver of adverse health and economic outcomes. The pathogenesis of mucositis is much more complex than previously hypothesized, involving more than a dozen mechanistic canonical pathways mediated by cells within the submucosa, as well as the epithelium. Furthermore, evidence suggests that the oral microflora does not play a primary role in the genesis of mucositis, although secondary infection might influence its course. Despite the prevalence of mucositis in cancer therapy, there is currently only one approved pharmaceutical for the treatment of oral mucositis: palifermin (keratinocyte growth factor-1) and its application is limited to mucositis associated with conditioning regimens for stem cell transplant for the treatment of hematologic malignancies; an indication that accounts for only 4% of the at risk population. Therefore, the care for mucositis i largely palliative and there is an urgent need for new, effective therapies for the broader patient population. Host defense proteins (HDPs) are cationic and amphiphilic components of the mammalian innate immune system that serve as a primary response in the prevention of bacterial infection. We are developing non- peptidic mimics of HDPs, capturing the structural and biological properties of HDPs within the framework of smaller inexpensive oligomers. These small synthetic oligomers are less expensive to produce, have better tissue distribution than HDPs, and are easier to fine-tune structurally to improve activity and minimize toxicity. Exclusive of their antimicrobial activity, HDPs have been shown to possess immune modulatory and anti- inflammatory activities. Recently, we observed that several of the PMX mimics demonstrate activity in attenuating anti-inflammatory pathways and reasoned that these activities could be leveraged into a mucositis intervention. Our hypothesis was borne out by the results of animal studies in which the severity and course of radiation-induced mucosal injury were dramatically altered after topical administration of three PMX mimics, including our lead compound PMX30063. The promising activity and observed tolerability of PMX30063, supports a dedicated effort for further preclinical profiling directed towards future clinical development. Accordingly, the overall goals of this Phase 1 proposal are to continue the preclinical development of PMX30063 for an oral mucositis indication by investigating its mechanism of action with a particular focus on anti-inflammatory and immune modulatory activities, optimizing its formulation as an oral rinse and helping to define dosing regimens for human clinical trials.
Public Health Relevance: Oral mucositis is among the most significant, dose-limiting side effects of intensive cancer treatment and is associated with adverse clinical and economic outcomes. It can cause difficulty with speaking, swallowing, and alimentation and radically impair daily functioning and quality of life and may necessitate opioid analgesia, a liquid diet, I hydration and/or total parenteral nutrition and interruption of cancer therapy. Standard management options for mucositis are essentially palliative. We propose to develop a novel topical anti-mucositis therapeutic to ameliorate this pernicious side effect of cancer therapy.
Public Health Relevance Statement: Oral mucositis is among the most significant, dose-limiting side effects of intensive cancer treatment and is associated with adverse clinical and economic outcomes. It can cause difficulty with speaking, swallowing, and alimentation and radically impair daily functioning and quality of life and may necessitate opioid analgesia, a liquid diet, I hydration and/or total parenteral nutrition and interruption of cancer therapy. Standard management options for mucositis are essentially palliative. We propose to develop a novel topical anti-mucositis therapeutic to ameliorate this pernicious side effect of cancer therapy.
NIH Spending Category: Biotechnology; Cancer; Dental/Oral and Craniofacial Disease; Infectious Diseases; Pain Conditions - Chronic; Pain Research
Project Terms: Absence of pain sensation; Accounting; Adverse effects; Affect; American; Analgesics; Animal Model; Animals; Anti-inflammatory; Anti-Inflammatory Agents; antimicrobial; Attenuated; Bacterial Infections; base; Biological; cancer radiation therapy; cancer therapy; Caring; Cell Culture System; cell type; Cells; chemotherapy; Clinical; Clinical Trials; Complex; conditioning; cost; Cost Savings; Cyclodextrins; daily functioning; Deglutition; design; Development; Diet; Dose; Dose-Limiting; Drug Formulations; Drug or chemical Tissue Distribution; economic outcome; effective therapy; Epithelium; Excipients; feeding; Freezing; Functional disorder; Future; Gastrostomy; Goals; Hamsters; Head and Neck Cancer; health economics; Hematologic Neoplasms; Host Defense; Human; Hydration status; Immune; Immune system; improved; In Vitro; in vivo; Inflammation; Inflammatory; Injury; insight; Interruption; Intervention; Investigation; keratinocyte growth factor; Lead; Liquid substance; Mediating; mimetics; Modeling; Mouth Neoplasms; Mucositis; Narcotics; novel; Opioid; Oral; oral mucositis; Oropharyngeal; Oxidative Stress; Pain; palliative; Pathogenesis; Pathway interactions; patient population; Patients; Peptides; Pharmacologic Substance; Phase; phase 1 study; Pilot Projects; Play; Populations at Risk; pre-clinical; Prevalence; Prevention; Property; Proteins; Quality of life; Radiation; Regimen; response; Role; Safety; secondary infection; Severities; Solubility; Staging; Stem cell transplant; Sterility; Submucosa; Testing; Therapeutic; Time; Topical application; Total Parenteral Nutrition; Toxic effect; Toxicity due to chemotherapy; Treatment Protocols
