A NOVEL IMPROVEMENT ON RADIOTHERAPY FOR SCCHN

头颈部鳞状细胞癌(SCCHN)，包括口腔鳞状细胞癌，死亡率高，复发率高。这些临床失败的很大一部分原因是肿瘤细胞辐射抵抗(RR)。因此，发展一种有效的方法使头颈部肿瘤对放射治疗增敏，将对该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凋亡途径中起着至关重要的作用。许多SCCHN肿瘤细胞中缺乏功能性P53被认为是导致RR的原因。WtP53功能的恢复可能会恢复P53介导的凋亡途径，从而导致更有效的治疗。Wtp53基因治疗和放射治疗的结合将用于恢复对RR SCCHN的辐射敏感性。癌症基因治疗的一个长期目标是一种全身性递送系统，它选择性地靶向肿瘤细胞，包括转移瘤。本申请建议优化wtp53的叶酸连接脂质体全身给药系统，以提高常规放射治疗的疗效。初步的体内实验结果已原则上证明wtp53功能的恢复可促进辐射诱导的细胞凋亡，从而导致长期的肿瘤整体消退。我们将与制药合作伙伴合作，获得GMP级试剂，进行毒理学和药代动力学研究，以获得IRB、IBC和FDA的批准。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应用于头颈部癌症的临床。

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.