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实验性癌症治疗，在临床前模型中产生了令人印象深刻的结果。尽管有这些令人鼓舞的结果，但这种方法在临床上的疗效有限，主要是由于体内基因转移的效率较低。为了克服这一限制，我们的研究项目开发了一种新颖的三模式方法，利用溶瘤、复制能力强的腺病毒，选择性地、有效地向肿瘤传递一对治疗性自杀基因。临床前研究表明，具有复制能力的腺病毒本身具有很强的抗肿瘤作用。通过激活两种自杀基因系统（CD/5-FC和HSV-1 TK/GCV），腺病毒的治疗效果可以显著增强，这两种基因系统使恶性细胞对特定药物敏感，更重要的是，使它们对辐射敏感。两项I期临床试验评估了复制能力腺病毒介导的双自杀基因治疗(不使用（BB-IND 8436）和使用（BB-IND 9852）三维适形放疗（3D-CRT）治疗前列腺癌男性的安全性和有效性，并取得了良好的结果。结果表明，复制能力腺病毒介导的双重自杀治疗可以安全地与常规剂量的3D-CRT联合使用，并显示出生物活性的迹象。这个项目建立在我们之前的临床前和临床成果的基础上，目标是发展复制能力腺病毒介导的双重自杀基因治疗技术，使其成为临床放射治疗的安全有效的辅助手段。为了实现这一目标，我们组建了一个高度互动的项目和核心小组，作为一个全面和有凝聚力的单位，将在三个方面推进gone治疗技术：1)通过开发更好的腺病毒载体和治疗基因，2)通过开发更好的载体传递和体内治疗性gone表达的监测手段，以及3)通过评估这些临床前进展在三个I/II期临床试验中的优点。这里所描述的基础科学和临床科学的结合将产生新的重要知识，并可能最终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.