A NOVEL IMPROVEMENT ON RADIOTHERAPY FOR SCCHN

SCCHN 放射治疗的新颖改进

• 批准号: 6175895
• 负责人: Esther H Chang
• 金额: $ 41.63万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6175895
• 关键词: apoptosis; athymic mouse; clinical research; clinical trial phase I; combination cancer therapy; drug delivery systems; drug design /synthesis /production; folate; head /neck neoplasm; histopathology; human subject; human therapy evaluation; liposomes; neoplasm /cancer radionuclide therapy; neoplasm /cancer transplantation; p53 gene /protein; radiation resistance; radiation sensitivity; radiosensitizer; squamous cell carcinoma

Squamous cell carcinoma of the head and neck (SCCHN), including that of the oral cavity, has a significant level of mortality and a high rate of recurrence. A significant portion of these clinical failures result from tumor cell radiation resistance (RR). Thus, the development of an effective method for sensitizing head and neck tumors to radiotherapy would have a profound effect on the treatment of this disease. Wild-type (wt) p53 plays a crucial role in apoptotic pathways leading to tumor cell death. The lack of functional p53 in many SCCHN tumor cells is thought to be responsible for their RR. The restoration of wtp53 function may restore the p53-mediated apoptotic pathway resulting in more efficient treatment. A combination of wtp53 gene therapy and radiation will be used to restore radiation sensitivity to RR SCCHN. A long-standing goal in gene therapy for cancer is a systemic delivery system that selectively targets tumor cells, including metastases. This application proposes to optimize a folate-linked liposome systemic delivery system for wtp53 to improve the efficacy of conventional radiotherapy. Preliminary in vivo results have proved in principle that restoration of wtp53 function enhances radiation induced apoptosis, leading to long term total tumor regression. In collaboration with a pharmaceutical partner, we will obtain GMP grade reagent, perform toxicology and pharmacokinetic studies to obtain IRB, IBC and FDA approval. Once approvals are obtained we will use this combination therapy in a Phase I clinical trial in an effort to translate this new and potentially more effective treatment modality into the clinic for head and neck cancer.

头颈鳞状细胞癌（SCCHN），包括口腔鳞状细胞癌，具有很高的死亡率和很高的复发率。 这些临床失败的很大一部分是由于肿瘤细胞耐辐射（RR）造成的。 因此，开发一种使头颈部肿瘤对放射治疗敏感的有效方法将对这种疾病的治疗产生深远的影响。 野生型 (wt) p53 在导致肿瘤细胞死亡的细胞凋亡途径中发挥着至关重要的作用。 许多 SCCHN 肿瘤细胞中缺乏功能性 p53 被认为是其 RR 的原因。 wtp53功能的恢复可能会恢复p53介导的细胞凋亡途径，从而导致更有效的治疗。 wtp53 基因治疗和放射治疗相结合将用于恢复 RR SCCHN 的放射敏感性。癌症基因治疗的一个长期目标是建立选择性靶向肿瘤细胞（包括转移瘤）的全身递送系统。 本申请提出优化 wtp53 的叶酸连接脂质体全身递送系统，以提高常规放疗的疗效。 初步体内结果原则上证明wtp53功能的恢复可增强辐射诱导的细胞凋亡，从而导致肿瘤的长期总体消退。 我们将与制药合作伙伴合作，获取 GMP 级试剂，进行毒理学和药代动力学研究，以获得 IRB、IBC 和 FDA 批准。 一旦获得批准，我们将在 I 期临床试验中使用这种联合疗法，努力将这种新的、可能更有效的治疗方式转化为头颈癌的临床。