Molecular Gene and Radiation Therapies for Cancer

癌症的分子基因和放射治疗

• 批准号: 7844634
• 负责人: SVEND O FREYTAG
• 金额: $ 1.87万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844634
• 关键词: Molecular; Gene; Radiation; Therapies; Cancer

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.

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性癌症疗法，已在临床前模型中产生了令人印象深刻的结果。 尽管取得了这些有希望的结果，但这种方法在临床上显示出的功效有限，这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，利用具有复制能力的溶瘤腺病毒选择性且有效地将一对治疗性自杀基因传递至肿瘤。 临床前研究表明，具有复制能力的腺病毒本身可以产生有效的抗肿瘤作用。 通过调用两个自杀基因系统（CD/5-FC和HSV-1 TK/GCV）可以显着增强腺病毒的治疗效果，这使得恶性细胞对特定的药物敏感，更重要的是，使它们对辐射敏感。两项 I 期临床试验已完成，评估了不使用（BB-IND 8436）和使用（BB-IND 9852）三维适形放射治疗（3D-CRT）的复制型腺病毒介导的双自杀基因疗法在男性前列腺癌患者中的安全性和有效性，并取得了优异的结果。结果表明，具有复制能力的腺病毒介导的双重自杀疗法可以与常规剂量的 3D-CRT 安全地结合，并且显示出生物活性的迹象。 该计划项目建立在我们之前的临床前和临床成就的基础上，只有一个目标：开发具有复制能力的腺病毒介导的双自杀基因治疗技术，使其成为临床上安全有效的放射治疗佐剂。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组，它们作为一个综合性和凝聚力的单元发挥作用，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手段和监测体内治疗性 gone 表达，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。这里描述的基础科学和临床科学相结合将产生新的重要知识，并可能最终带来更有效的癌症治疗。

项目成果

Gene therapy strategies to enhance the effectiveness of cancer radiotherapy.

提高癌症放射治疗效果的基因治疗策略。

• 发表时间: 2004
• 期刊: Current opinion in molecular therapeutics.
• 作者: Freyta,SvendO;Kim,JaeHo;Brown,StephenL;Barton,Kenneth;Lu,Mei;Chung,Myung
• 通讯作者: Chung,Myung

A novel method of boron delivery using sodium iodide symporter for boron neutron capture therapy.

• DOI: 10.1269/jrr.10036
• 发表时间: 2010
• 期刊: Journal of radiation research
• 影响因子: 2
• 作者: Kumar S;Freytag SO;Barton KN;Burmeister J;Joiner MC;Sedghi B;Movsas B;Binns PJ;Kim JH;Brown SL
• 通讯作者: Brown SL

Phase I study of noninvasive imaging of adenovirus-mediated gene expression in the human prostate.

• DOI: 10.1038/mt.2008.172
• 发表时间: 2008-10
• 期刊: Molecular therapy : the journal of the American Society of Gene Therapy

Does hyperthermia increase adenoviral transgene expression or dissemination in tumors?

• DOI: 10.1080/02656730902913248
• 发表时间: 2009-06
• 期刊: International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
• 作者: Siddiqui F;Kolozsvary A;Barton KN;Freytag SO;Brown SL;Kim JH
• 通讯作者: Kim JH

Polyethylene glycol (molecular weight 400 DA) vehicle improves gene expression of adenovirus mediated gene therapy.

聚乙二醇（分子量 400 DA）载体可改善腺病毒介导的基因治疗的基因表达。

• DOI: 10.1016/s0022-5347(05)00918-3
• 发表时间: 2006
• 期刊: The Journal of urology.
• 作者: Barton,KN;Stricker,H;Kolozsvary,A;Kohl,R;Heisey,G;Nagaraja,TN;Zhu,G;Lu,M;Kim,JH;Freytag,SO;Brown,SL
• 通讯作者: Brown,SL