Smad7 use in oral mucositis treatment

Smad7在口腔粘膜炎治疗中的应用

• 批准号: 8779526
• 负责人: BRIAN Curtis TURNER
• 金额: $ 18.63万
• 依托单位: TAIGA BIOTECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8779526
• 关键词: Acute; Address; Adult; Adverse effects; Affect; Animals; Biochemical; C57BL/6 Mouse; Cancer Cell Growth; Cancer Patient; Cancer cell line; Canis familiaris; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Chimeric Proteins; Chronic; Codon Nucleotides; Data; Diagnosis; Dose; Drug Kinetics; Endotoxins; Escherichia coli; Excision; FDA approved; Flow Cytometry; Future; Genetically Engineered Mouse; Goals; HIV-1; Healed; Human; Individual; Intensity-Modulated Radiotherapy; Lesion; Malignant Neoplasms; Measurement; Measures; Methods; Mus; Neoplasm Metastasis; Normal tissue morphology; Oral; Oral Ulcer; Oral cavity; Oral mucous membrane structure; Pain; Patients; Peptide Synthesis; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology and Toxicology; Phase; Phosphorylation; Population; Post-Translational Protein Processing; Procedures; Process; Production; Proteins; Protocols documentation; Radiation; Radiation therapy; Radio; Recombinant Proteins; Recombinants; Safety; Scientist; Smad7 protein; Small Business Innovation Research Grant; System; Testing; Therapeutic; Therapeutic Effect; Tongue; Toxic effect; Transplantation; Ulcer; United States; cancer cell; cancer radiation therapy; cancer therapy; chemoradiation; commercialization; craniofacial; healing; improved; in vivo; killings; malignant mouth neoplasm; meetings; novel therapeutics; oncology; oral mucositis; phase 1 study; phase 2 study; pre-clinical; prevent; prophylactic; public health relevance; repaired; research and development; research study; screening; tat Protein; transduction efficiency; tumor; tumor growth

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.

口腔黏膜炎是一种严重的口腔溃疡，是放射线或放化疗常见的毒性作用，也是使用最大剂量辐射进行有效癌症治疗的限制因素。在美国，大约有1790万成年人被诊断患有癌症，占总人口的7.9%。接受标准化疗方案或上半身放射治疗的患者中，至少40%至70%会发生口腔黏膜炎。到目前为止，还没有FDA批准的药物用于治疗癌症患者的口腔黏膜炎。口腔黏膜炎治疗的关键挑战是修复和保护溃疡的口腔黏膜，而不促进癌细胞的生长。Drs。Wang和Zhang与Taiga的科学家Refaeli博士合作开发了一种Smad7融合蛋白，其中包含与HIV-1 Tat蛋白转导结构域（PTD）融合的人类Smad7。Tat-Smad-7蛋白可以快速穿透细胞。Tat-Smad7局部应用于小鼠口腔黏膜，对放射性口腔黏膜炎有预防和治疗作用。我们的长期目标是开发Tat-Smad7作为治疗性生物制剂，以预防和治疗癌症患者的放射性口腔黏膜炎。目的1将优化蛋白的生产和纯化系统，建立量化方法来测量Tat-Smad7蛋白的转导效率和生化活性。这些研究将使我们能够开发一个生产平台，并标准化Tat-Smad7的生化定量，用于II期研究和未来的患者应用。目的2将解决治疗癌症患者口腔黏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性生物制剂，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开发的小鼠SCC细胞系原位移植到同源C57BL/6小鼠的舌头上，并将这些肿瘤小鼠暴露于颅面辐射以诱导口腔粘膜炎。Aim 1中产生的Tat-Smad7将应用于口腔，因此口腔粘膜炎和癌细胞都是由Tat-Smad7转导的。在Tat-Smad7有效剂量范围内，我们的目标是确定Tat-Smad7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-Smad7在治疗放射性口腔黏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II期申请进行这些ind启用研究。