Oral mucositis, a severe oral ulceration, is a common toxic effect of radio- or chemoradio-therapy and a limiting factor to using the maximum dose of radiation for effective cancer treatment. About 17.9 million adults have been diagnosed with cancer in the United States, which is ~7.9% of the total population. At least 40%, and up to 70%, of individuals treated with standard chemotherapy regimens or upper-body radiation develop oral mucositis. To date, there is no FDA approved drug to treat oral mucositis in cancer patients. The key challenge for oral mucositis treatment is to repair and protect ulcerated oral mucosa without promoting cancer cell growth. Drs. Wang and Zhang have collaborated with Taiga's scientist Dr. Refaeli to develop a Smad7 fusion protein containing human Smad7 fused to the HIV-1 Tat protein transduction domain (PTD). The Tat-Smad-7 protein can rapidly penetrate cells. Local Tat-Smad7 application to mouse oral mucosa shows prophylactic and therapeutic effects on radiation-induced oral mucositis. Our long-term goal is to develop Tat-Smad7 as a therapeutic biologic to prevent and treat radiation-induced oral mucositis in cancer patients.
Aim 1 will optimize the protein production and purification system and establish quantification methods for measuring the efficiency of Tat-Smad7 protein transduction and biochemical activities. These studies will allow us to develop a production platform and standardize biochemical quantification of Tat-Smad7 for Phase II studies and future use in patients.
Aim 2 will address one of the most important toxicity issues of treating oral mucositis in cancer patients, i.e., to provide evidence if Tat-Smad7 can be used as a therapeutic biologic to protect normal oral mucosa without compromising radiation-induced killing of cancer cells. We will orthotopically transplant mouse SCC cell lines developed in Dr. Wang's lab into the tongue of syngeneic C57BL/6 mice and expose these tumor-bearing mice to craniofacial radiation to induce oral mucositis. Tat-Smad7 produced in Aim 1 will be applied to the oral cavity so both oral mucositis and cancer cells are transduced by Tat-Smad7. Among the Tat-Smad7 effective dose range, we aim to identify Tat-Smad7 doses that do not protect cancer from radiotherapy. The proposed studies will allow us to meet commercial needs for protein production and provide critical preclinical data on the safety and efficacy of Tat-Smad7 in a therapeutic setting for radiation-induced oral mucositis. We plan to perform these IND-enabling studies via a Phase II application after completing the current application.
Oral mucositis, a painful oral ulceration, is one of the most severe toxicities of cancer therapy. This application produces and tests a novel therapeutic biologic for treating oral mucositis without compromising radiotherapy in cancer patients.
|Luo, Jingjing; Bian, Li; Blevins, Melanie A et al. (2018) Smad7 Promotes Healing of Radiotherapy-Induced Oral Mucositis without Compromising Oral Cancer Therapy in a Xenograft Mouse Model. Clin Cancer Res :|