Smad7 use in oral mucositis treatment

口腔粘膜炎是一种严重的口腔溃疡，是放射或化学放射治疗的常见毒性作用，也是使用最大剂量放射进行有效癌症治疗的限制因素。在美国，约有1790万成年人被诊断患有癌症，占总人口的7.9%。至少有40%，高达70%的人用标准化疗方案或上半身放射治疗发展口腔粘膜炎。迄今为止，还没有FDA批准的药物用于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修复和保护溃疡的口腔粘膜而不促进癌细胞生长。Wang博士和Zhang博士与Taiga的科学家Refaeli博士合作开发了一种Smad 7融合蛋白，该蛋白含有与HIV-1达特蛋白转导结构域（PTD）融合的人Smad 7。Tat-Smad-7蛋白可以快速穿透细胞。将Tat-Smad 7局部应用于小鼠口腔粘膜显示出对放射诱导的口腔粘膜炎的预防和治疗效果。我们的长期目标是开发Tat-Smad 7作为治疗生物制剂，以预防和治疗癌症患者放射性口腔粘膜炎。目的1优化Tat-Smad 7蛋白的生产和纯化体系，建立Tat-Smad 7蛋白转导效率和生化活性的定量检测方法。这些研究将使我们能够开发一个生产平台，并标准化Tat-Smad 7的生化定量，用于II期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的最重要的毒性问题之一，即，提供证据证明Tat-Smad 7是否可以用作治疗生物制剂，以保护正常口腔粘膜，而不损害辐射诱导的癌细胞杀伤。我们将在王博士的实验室中开发的小鼠SCC细胞系原位移植到同系C57 BL/6小鼠的舌头中，并将这些荷瘤小鼠暴露于颅面辐射以诱导口腔粘膜炎。在Aim 1中产生的Tat-Smad 7将被应用于口腔，因此口腔粘膜炎和癌细胞都被Tat-Smad 7转导。在Tat-Smad 7有效剂量范围内，我们的目标是确定Tat-Smad 7剂量不能保护癌症免受放射治疗。拟议的研究将使我们能够满足蛋白质生产的商业需求，并提供关于Tat-Smad 7在辐射诱导的口腔粘膜炎治疗环境中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II期申请进行这些IND使能研究。

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.