Translational Applications of mda-7/IL-24 in Cancer

mda-7/IL-24 在癌症中的转化应用

• 批准号: 7683897
• 负责人: PAUL B FISHER
• 金额: $ 135.35万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-19 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683897
• 关键词: Translational; Applications; mda; IL; 24

DESCRIPTION (provided by applicant): The long-term objectives of our research programs are to develop an improved understanding and define enhanced translational applications for a novel gene, mda-7/IL-24, with significant clinical potential as an anticancer gene therapeutic. Subtraction hybridization identified the cancer-selective apoptosis-inducing cytokine gene, mda-7/IL-24, which displays antiproliferative and programmed cell death promoting activities in a wide spectrum of histologically distinct human cancers. In contract, mda-7/IL-24 produces no harmful effects in normal cells. Based on these promising attributes, Phase I/II clinical trials were performed to assess safety of mda-7/IL-24 in patients. When administered intratumorally in patients with advanced carcinomas and malignant melanomas by means of a replication incompetent adenovirus, Ad.mda-7 (INGN 241) was shown to be safe, without significant side effects, and to induce apoptosis in a majority of the tumor mass after a single injection of virus. These exciting findings provide support for aggressively evaluating mda-7/IL-24 for cancer gene therapy. The specific aims of this PPG are to expand on the provocative basic science studies and the early clinical successes of mda-7/IL-24 to accelerate its translational applications in three cancer indications, prostate cancer, glioblastoma multiforme and ovarian cancer. To achieve these objectives, a team of established investigators has been assembled with documented experience in cancer cell biology, cancer gene therapy, oncology and radiation biology. Support is requested for definitive studies that will lead to improved translational applications of mda-7/IL-24 in prostate, glioblastoma multiforme and ovarian cancer. We are also requesting administrative support for the Program Project and support for two core resource facilities, one for producing purified MDA-7/IL-24 protein (which like the gene display cancer-specific apoptosis inducing properties) and one for producing genetically engineered viruses expressing mda-7/IL-24, to facilitate studies by members of the Program Project team. The individual interactive projects and cores and their objectives are: Project 1: Develop improved therapeutic applications of mda-7/IL-24 in prostate cancer. This project will focus on defining regions of mda-7/IL-24 mediating its apoptosis inducing effects; developing improved methods for delivering and expressing mda-7/Il-24 in prostate cancer cells; and preclinical animal studies to define potential efficacy of new infectivity enhanced viruses targeting prostate cancer cells and producing mda-7/IL-24. (Fisher) Project 2: Develop improved therapeutic applications of mda-7/IL-24 in malignant gliomas. This project will focus on defining the mechanism by which MDA-7 protein and Ad.mda-7 radiosensitize human malignant gliomas to lose viability and to determine preclinical efficacy in pre-existing tumors in the rat brain. (Dent) Project 3: Develop improved "complex mosaic" adenoviruses to improved delivery of mda-7/IL-24 into and study the effects on ovarian cancer cells in vitro and in vivo in nude mice. (Curiel) Core A: Produce purified MDA-7 protein for mechanistic studies proposed in Projects 1, 2 and 3. (Gupta) Core B: Produce recombinant adenoviruses for mechanistic studies proposed in Projects 1, 2 and 3. (Curiel) Core C: To provide administrative support for this program project grant. (Fisher)

描述（由申请人提供）： 我们的研究计划的长期目标是开发一个新的基因，mda-7/IL-24，具有显着的临床潜力作为抗癌基因治疗的理解和定义增强翻译应用。消减杂交鉴定了癌症选择性凋亡诱导细胞因子基因mda-7/IL-24，其在广泛的组织学上不同的人类癌症中显示抗增殖和程序性细胞死亡促进活性。 相比之下，mda-7/IL-24在正常细胞中不产生有害作用。基于这些有希望的属性，进行I/II期临床试验以评估mda-7/IL-24在患者中的安全性。 当通过无复制能力的腺病毒在晚期癌和恶性黑素瘤患者中瘤内施用时，Ad.mda-7（INGN 241）显示出是安全的，没有显著的副作用，并且在单次注射病毒后在大多数肿瘤块中诱导细胞凋亡。 这些令人兴奋的发现为积极评估mda-7/IL-24用于癌症基因治疗提供了支持。 该PPG的具体目标是扩展mda-7/IL-24的挑衅性基础科学研究和早期临床成功，以加速其在三种癌症适应症（前列腺癌，多形性胶质母细胞瘤和卵巢癌）中的转化应用。 为了实现这些目标，组建了一支由在癌细胞生物学、癌症基因治疗、肿瘤学和放射生物学方面拥有丰富经验的知名研究人员组成的团队。 需要支持明确的研究，这将导致改善翻译应用的mda-7/IL-24在前列腺癌，多形性胶质母细胞瘤和卵巢癌。 我们还请求对该计划项目提供行政支持，并支持两个核心资源设施，一个用于生产纯化的MDA-7/IL-24蛋白（类似于显示癌症特异性细胞凋亡诱导特性的基因），另一个用于生产表达mda-7/IL-24的基因工程病毒，以促进计划项目团队成员的研究。 各个互动项目和核心及其目标是： 项目1：开发改进的mda-7/IL-24在前列腺癌中的治疗应用。 该项目将专注于确定mda-7/IL-24介导其凋亡诱导作用的区域;开发在前列腺癌细胞中递送和表达mda-7/IL-24的改进方法;以及临床前动物研究，以确定靶向前列腺癌细胞并产生mda-7/IL-24的新型感染性增强病毒的潜在功效。（费舍尔） 项目2：开发改进的mda-7/IL-24在恶性胶质瘤中的治疗应用。 该项目将重点确定MDA-7蛋白和Ad.mda-7放射增敏人类恶性胶质瘤失去活力的机制，并确定在大鼠脑中既存肿瘤中的临床前疗效。（凹痕） 项目三：开发改良的“复合嵌合体”腺病毒以改善mda-7/IL-24进入卵巢癌细胞的递送，并在体外和裸鼠体内研究对卵巢癌细胞的作用。（库里尔） 核心A：生产纯化的MDA-7蛋白，用于项目1、2和3中提出的机制研究。（古普塔） 核心B：生产重组腺病毒，用于项目1、2和3中提出的机制研究。（库里尔） 核心C：为该项目提供行政支持。（费舍尔）

项目成果

Innovative approaches for enhancing cancer gene therapy.

• 发表时间: 2013-05
• 期刊: Discovery medicine
• 影响因子: 1.4
• 作者: Shilpa Bhatia;M. E. Menezes;Swadesh K. Das;L. Emdad;S. Dasgupta;Xiang-Yang Wang;D. Sarkar;P. Fisher

Astrocyte elevated gene-1 (AEG-1): A multifunctional regulator of normal and abnormal physiology.

• DOI: 10.1016/j.pharmthera.2011.01.008
• 发表时间: 2011-04
• 期刊: PHARMACOLOGY & THERAPEUTICS
• 影响因子: 13.5
• 作者: Yoo, Byoung Kwon;Emdad, Luni;Lee, Seok-Geun;Su, Zao-zhong;Santhekadur, Prasanna;Chen, Dong;Gredler, Rachel;Fisher, Paul B.;Sarkar, Devanand
• 通讯作者: Sarkar, Devanand

Chimeric adenoviral vectors incorporating a fiber of human adenovirus 3 efficiently mediate gene transfer into prostate cancer cells.

• DOI: 10.1002/pros.21070
• 发表时间: 2010-03-01
• 期刊: PROSTATE
• 影响因子: 2.8
• 作者: Murakami, Miho;Ugai, Hideyo;Belousova, Natalya;Pereboev, Alexander;Dent, Paul;Fisher, Paul B.;Everts, Maaike;Curiel, David T.
• 通讯作者: Curiel, David T.

Chemoprevention gene therapy (CGT): novel combinatorial approach for preventing and treating pancreatic cancer.

化学预防基因疗法（CGT）：预防和治疗胰腺癌的新型组合方法。

• DOI: 10.2174/1566524011313070008
• 发表时间: 2013
• 期刊: Current molecular medicine
• 影响因子: 2.5
• 作者: Sarkar,S;Azab,BM;Das,SK;Quinn,BA;Shen,X;Dash,R;Emdad,L;Thomas,S;Dasgupta,S;Su,Z-Z;Wang,X-Y;Sarkar,D;Fisher,PB
• 通讯作者: Fisher,PB

Characterization of the canine mda-7 gene, transcripts and expression patterns.

犬 mda-7 基因、转录本和表达模式的表征。

• DOI: 10.1016/j.gene.2014.05.054
• 发表时间: 2014
• 期刊: Gene
• 影响因子: 3.5
• 作者: Sandey,Maninder;Bird,RCurtis;Das,SwadeshK;Sarkar,Devanand;Curiel,DavidT;Fisher,PaulB;Smith,BruceF
• 通讯作者: Smith,BruceF