A Topical Nrf Activator for Oral Mucositis

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 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 patientandapos 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$ 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 PB that activates the Nrf NFE L Nuclear Factor Erythroid Like 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 Nrf activating properties of PB in a variety of cell types have identified and tested a backup agent from the same molecular class in case PB fails during development and have created a prototype of the intended aqueous oral formulation of PB Briefly our preliminary data supports the hypothesis the PB is a potent Nrf 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 PB examine Nrf activation and gene expression caused by the PB formulation in cultured human oral mucosal cells and perform efficacy studies of the topically applied PB 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 PB 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 Oral mucositis is a harmful and painful side effect of radiation therapy and chemotherapy that affects nearly half a million cancer patients in the US each year and that can be dose limiting impairing the clinical ability to continue the otherwise needed No effective treatments are available and there is a great unmet need to develop new therapeutic approaches to oral mucositis In the present study a new topical agent will be tested and developed to pursue the promising approach of protecting the oral mucosal cells through the application of topical agents that upregulate cell protection mechanisms in the oral mucosa prior to radiation or chemotherapy