Molecular Gene and Radiation Therapies for Cancer

描述（由申请人提供）：腺病毒介导的自杀基因疗法是一种研究癌症疗法，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显示出有限的功效，这主要是由于体内基因转移效率低。 为了克服这一局限性，我们的研究项目开发了一种新的三模式方法，该方法利用溶瘤的、有复制能力的腺病毒选择性地、有效地将一对治疗性自杀基因递送到肿瘤。 临床前研究已经证明，具有复制能力的腺病毒本身产生有效的抗肿瘤作用。 腺病毒的治疗效果可以通过调用两个自杀基因系统（CD/5-FC和HSV-1 TK/GCV）来显著增强，这使得恶性细胞对特定的药理学试剂敏感，并且重要的是，使它们对辐射敏感。两个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的安全性和有效性，没有（BB-IND 8436）和（BB-IND 9852）三维适形放射治疗（3D-CRT）的前列腺癌男性已经完成了良好的结果。结果表明，复制型腺病毒介导的双重自杀基因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，具有单一的目标-开发复制能力的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有效的佐剂。为了实现这一目标，我们已经组建了一个高度互动的项目和核心组，作为一个全面和有凝聚力的单元，将在三个方面推进Gone Therapy技术：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表达的监测手段，和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.