Smad7 use in oral mucositis treatment

描述(申请人提供)：口腔粘膜炎是一种严重的口腔溃疡，是放化疗的一种常见毒性反应，也是限制使用最大剂量辐射进行有效癌症治疗的一个限制因素。在美国，大约有1790万成年人被诊断出患有癌症，约占总人口的7.9%。在接受标准化疗方案或上半身放射治疗的患者中，至少有40%、高达70%的人会患上口腔粘膜炎。到目前为止，还没有FDA批准的药物来治疗癌症患者的口腔粘膜炎。口腔粘膜炎治疗的关键挑战是在不促进癌细胞生长的情况下修复和保护溃烂的口腔黏膜。王博士和张博士与Taiga的科学家Refaeli博士合作开发了一种Smad7融合蛋白，该融合蛋白含有融合到HIV-1 Tat蛋白转导结构域(PTD)的人Smad7。TAT-Smad-7蛋白可以快速穿透细胞。小鼠口腔黏膜局部应用TAT-Smad7对放射性口腔粘膜炎有预防和治疗作用。我们的长期目标是开发TAT-Smad7作为一种治疗生物学，用于预防和治疗癌症患者放射性口腔粘膜炎。目的1优化蛋白质生产和纯化系统，建立测定TAT-Smad7蛋白转导效率和生化活性的定量方法。这些研究将使我们能够开发一个生产平台，并标准化TAT-Smad7的生化量化，用于第二阶段研究和未来在患者中的使用。目的2将解决治疗癌症患者口腔粘膜炎最重要的毒性问题之一，即提供证据，证明TAT-Smad7是否可以作为一种治疗生物材料，在不影响辐射诱导的癌细胞杀伤的情况下保护正常口腔黏膜。我们将把王博士实验室培育的小鼠SCC细胞系原位移植到同基因C57BL/6小鼠的舌内，并将这些荷瘤小鼠暴露于头面部放射诱导口腔粘膜炎。在AIM 1中生产的TAT-Smad7将应用于口腔，因此口腔粘膜炎和癌细胞都由TAT-Smad7转导。在TAT-Smad7有效剂量范围中，我们的目标是确定不能保护癌症免受放射治疗的TAT-Smad7剂量。拟议的研究将使我们能够满足蛋白质生产的商业需求，并提供有关TAT-Smad7在治疗放射性口腔粘膜炎方面的安全性和有效性的关键临床前数据。我们计划在完成当前申请后，通过第二阶段申请进行这些启用IND的研究。

DESCRIPTION (provided by applicant): Summary 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.