We propose to develop a topical formulation for preventing or treating oral mucositis. Oral mucositis is a common and harmful side effect of radiation therapy and chemotherapy in cancer patients that affects nearly 500,000 patients in the US annually and can be dose-limiting, impairing the clinical ability to continue the otherwise needed therapy and that also greatly impacts the patient's quality of life due to pain, loss of function, and increased infections. There remains a huge unmet clinical need, with a market value of approximately US$1 billion. Despite the high frequency of oral mucositis in both radiation and chemotherapy patients, its negative impact on the clinical ability to apply sufficient doses of these therapies to patients, its debilitating nature on the affected patients, and the associated high financial costs of oral mucositis per patient, there is no effective intervention currently available for the majority of patients at risk. One promising approach is protecting the oral mucosal cells through the application of topical agents that upregulate cell protection mechanisms in the oral mucosa prior to radiation therapy. We are developing a therapeutic agent (PB201) that activates the Nrf2 (NFE2L2, Nuclear Factor Erythroid 2-Like 2) cell signaling pathway which in turn upregulates radioprotective, antioxidant, and anti-inflammatory genes and is a promising candidate for preventing or treating oral mucositis. We have examined the Nrf2 activating properties of PB201 in a variety of cell types, have identified and tested a backup agent from the same molecular class in case PB201 fails during development, and have created a prototype of the intended aqueous oral formulation of PB201. Briefly, our preliminary data supports the hypothesis the PB201 is a potent Nrf2 activator in a variety of cancer and normal human cell types and is a strong candidate for development as a topical oral mucositis drug. In Phase I of this multiphase project, we will create and test a topical formulation of PB201, examine Nrf2 activation and gene expression caused by the PB201 formulation in cultured human oral mucosal cells, and perform efficacy studies of the topically-applied PB201 formulation in a hamster model of radiation- induced oral mucositis. Our preliminary data suggests that the likelihood for success is high in this Phase I project, and we are planning to continue the work in a Phase II SBIR project including expansion into fractionated radiation and chemotherapy models of oral mucositis and ADME and toxicological measurements as we develop PB201 in an attempt to meet the unmet need for new therapeutic approaches to oral mucositis. Development of safe, effective, topical treatment that upregulates cell protection mechanisms in the oral mucosa prior to or after radiation or chemotherapy would be a significant advancement.

R43DE026086

2017-03-15

2018-12-14