Molecular Gene and Radiation Therapies for Cancer

描述(由申请人提供)：腺病毒药物自杀基因治疗是一种调查癌症治疗方法，在临床前模型中产生了令人印象深刻的结果。尽管有这些有希望的结果，但这种方法在临床上表现出的效果有限，这主要是因为体内基因转移的效率很低。为了克服这一限制，我们的研究计划开发了一种新颖的三模式方法，利用一种溶瘤的、具有复制能力的腺病毒来选择性和有效地将一对治疗性自杀基因输送到肿瘤。临床前研究表明，具有复制能力的腺病毒本身就能产生强大的抗肿瘤作用。通过调用两个自杀基因系统(CD/5-FC和HSV-1 TK/GCV)，可以显著提高腺病毒的治疗效果，这两个系统使癌细胞对特定的药理物质敏感，更重要的是，使它们对辐射敏感。两个I期临床试验已经完成，评估了增殖型腺病毒介导的双自杀基因治疗(BB-IND 8436)和三维适形放射治疗(BB-IND 9852)对前列腺癌男性患者的安全性和有效性，并获得了良好的结果。结果表明，复制型腺病毒介导的双自杀治疗可以安全地与常规剂量的3D-CRT相结合，并显示出生物活性的迹象。该计划项目建立在我们以前的临床前和临床成就的基础上，有一个共同的目标--开发复制型腺病毒介导的双自杀基因治疗技术，使其成为临床放射治疗的安全和有效的辅助手段。为了实现这一目标，我们组建了一组高度互动的项目和核心，这些项目和核心将在三个方面推动Gone治疗技术的发展：1)通过开发更好的腺病毒载体和治疗性基因，2)通过开发更好的载体递送和体内治疗性Gone表达监测方法，以及3)通过在三个I/II期临床试验中评估这些临床前进展的优点。这里描述的基础和临床相结合的科学将产生新的重要知识，并最终可能导致更有效的癌症治疗。

DESCRIPTION (provided by applicant): Adenovirus-medicated suicide gene therapy is an investigation cancer therapy that has produced impressive results in preclinical models. Despite these promising results, this approach has shown limited efficacy in the clinic largely due to a low efficiency of gene transfer in vivo. To overcome this limitation, our research program has developed a novel, trimodal approach that utilizes an oncolytic, replication-competent adenovirus to selectively and efficiently deliver a pair of therapeutic suicide genes to tumors. Preclinical studies have demonstrated that the replication-competent adenovirus itself generates a potent anti-tumor effect. The therapeutic efficacy of the adenovirus can be enhanced significantly by invoking two suicide gene systems (CD/5-FC and HSV-1 TK/GCV), which render malignant cells sensitive to specific pharmacological agents and, importantly, sensitizes them to radiation. Two phase I clinical trials that evaluated the safety and efficacy of replication-competent adenovirus-mediated double suicide gene therapy without (BB-IND 8436) and with (BB-IND 9852) three-dimensional conformal radiotherapy (3D-CRT) in men with prostate cancer have been completed with excellent results. The results demonstrate that replication-competent adenovirus-mediated double suicide gone therapy can be combined safely with conventional dose 3D-CRT and is showing signs of biological activity. This Program Project builds on our previous preclinical and clinical accomplishments with a single-minded goal- to develop the technology of replication-competent adenovirus-mediated double suicide gene therapy to a point where it will be a safe and effective adjuvant to radiation therapy in the clinic. To accomplish this, we have assembled a highly interactive group of projects and cores that function as a comprehensive and cohesive unit that will advance gone therapy technology on three fronts: 1) by developing better adenoviral vectors and therapeutic genes, 2) by developing better means of vector delivery and monitoring of therapeutic gone expression in vivo, and 3) by evaluating the merit of these preclinical advancements in three Phase I/II clinical trials. The combined basic and clinical science described here will generate new important knowledge and may ultimately lead to more effective cancer treatments.