Intratumoral generation of F-Ade to ablate low growth fraction HNSCC

这项研究将介绍一种新的肿瘤细胞杀伤方法，旨在以低成本消融实体瘤 增殖指数和伴随而来的肿瘤前体细胞。我们实验室一直在追踪2-氟腺嘌呤 脱氧核糖核酸(F-Ade)，一种嘌呤碱基，可破坏DNA、RNA和蛋白质的合成，是一种抗癌化合物。在这里，我们 利用F-araAMP，一种临床批准的药物，否则对实体肿瘤的活性可以忽略不计，作为F- ADE前驱体。F-ADE是由氟达拉滨通过瘤内表达大肠杆菌嘌呤核苷而产生的 磷酸酶(PNP)基因。该策略在综合性非临床应用中显示出显著的疗效。 最近完成的头颈部鳞状细胞癌(HNSCC)的研究和首例人体试验。 目前这项提案的科学目标是基于以下因素建立强大而安全的肿瘤消退 体外和体内多种HNSCC肿瘤类型的活性，并增加PNP的递送和安全性 基因(特异性目标1和2)。实验将评估作用机制(核苷裂解，PNP 转基因活性，破坏非周期肿瘤细胞隔间)(特定目标3)。我们的实验 计划是多学科的(生物医学工程、纳米化学、DNA/RNA递送技术、 核苷新陈代谢和酶学)，相辅相成，并由一名受过 肿瘤学(Sorscher)和生物医学工程科学家开始了他的研究生涯(Dahlman)。 转化潜力很高，这一技术的成功第一阶段试验表明，正式的孤儿药物 指定，以及FDA批准的第二阶段研究。

This study will address a novel tumor cell killing approach designed to ablate solid tumors with a low proliferative index and the attendant neoplastic progenitor cells. Our laboratory has pursued 2-Fluoroadenine (F-Ade), a purine base that disrupts DNA, RNA, and protein synthesis, as an anticancer compound. Here, we utilize F-araAMP, a clinically approved drug that otherwise has negligible activity against solid tumors, as an F- Ade precursor. F-Ade is generated from fludarabine by intratumoral expression of the E. coli purine nucleoside phosphorylase (PNP) gene. The strategy has demonstrated significant efficacy in comprehensive nonclinical studies and a recently completed, first-in-human trial of head and neck squamous cell carcinoma (HNSCC). The scientific objectives of the current proposal are to establish strong and safe tumor regressions based on activity across multiple HNSCC tumor types in vitro and in vivo, and to augment delivery and safety of the PNP gene (Specific Aims 1 and 2). The experiments will evaluate mechanism of action (nucleoside cleavage, PNP transgene activity, disruption of the noncycling tumor cell compartment) (Specific Aim 3). Our experimental plan is multidisciplinary (biomedical engineering, nanoparticle chemistry, DNA/RNA delivery technology, nucleoside metabolism and enzymology), mutually reinforcing, and directed by a senior investigator trained in oncology (Sorscher) and a biomedical engineering scientist beginning his research career (Dahlman). Translational potential is high, as indicated by a successful Phase 1 trial of the technology, formal orphan drug designation, and a Phase 2 study approved by FDA.