MDA-7/IL-24: Therapy of Prostate Cancer

MDA-7/IL-24：前列腺癌的治疗

• 批准号: 7007045
• 负责人: PAUL B FISHER
• 金额: $ 27.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7007045
• 关键词: Adenoviridae; BCL2 gene /protein; apoptosis; athymic mouse; clinical research; cytokine; gene therapy; human tissue; metastasis; neoplasm /cancer genetics; neoplasm /cancer immunotherapy; neoplastic process; prostate neoplasms; recombinant virus; transfection /expression vector

Despite intensive research, no single therapeutic approach has proven very successful in effecting a long-term cure of prostate cancer, even when disease is initially detected as a localized focus. Androgen ablation, prostatectomy or radiotherapy are at best palliative and have drastic consequences on post-treatment quality of life. Current statistics indicate a high frequency of recurrence accompanied by aggressive metastasis within relatively short periods after radical therapeutic intervention. A gene therapy based approach represents promising alternative therapeutic prospects in the prevailing scenario of limited survival benefits with conventional treatment. Subtraction hybridization identified a novel gene, melanoma differentiation associated gene-7. Based on structural and functional homology to interleukin-10, mda-7 has been recently redesignated as IL-24. mda-7/IL24 when expressed by means of a replication incompetent adenovirus, Ad.mda-7, suppresses growth and reduces viability by inducing apoptosis in a broad spectrum of cancers, including prostate carcinomas. In contrast, Ad.mda-7 does not produce harmful effects in a spectrum of normal cell types. These observations have been extended to the clinical setting indicating that Ad.mda-7 is safe and a single intratumoral injection in patients with advanced carcinomas and melanomas results in apoptosis in a high percentage (> 70%) of the tumor and repeated doses have produced objective clinical responses. As seen with Ad.mda-7, purified GST-MDA-7 fusion protein also induces apoptosis when applied to cancer cells, including prostate carcinomas, but not to normal cells. These unique cancer-specific apoptosis inducing properties suggest that mda-7/IL-24 is a strong candidate cancer gene therapeutic for treatment of primary prostate tumors as well as metastases. Understanding the mechanism by which mda-7/IL-24 induces its anti-prostate carcinoma specific effect will define ways of enhancing its activity, determining safety parameters and thereby facilitate the likelihood of transferring this molecule into the clinic for this cancer. Based on very promising recent findings, studies will be performed to: Specific Aim 1: Investigate the basis of mda-7/IL-24 prostate cancer specific apoptosis inducing properties. Experiments will define structure/function relationships through mutagenesis. Given the potentially central role of BCL-2 and BCL-xL in prostate cancer development, we will determine their importance in regulating sensitivity of prostate carcinoma cells to mda 7/IL-24. Experiments will be performed in collaboration with Dr. Dent (Project 2) to define the role of specific signal transduction pathways and ionizing radiation in regulating Ad.mda-7 protein mediated induction of apoptosis in prostate cancer cells. Specific Aim 2: Develop a novel, innovative gene therapy approach that will enhance the clinical utility of mda-8/IL-24 for the therapy of prostate cancer. A novel Triage Virus will be made in collaboration with Dr. Curiel. (Project 3, CoreB)with modified infectivity properties resulting from fiber/penton modifications (complex mosaic), prostate cancer-specific replication using the progression elebated gene-3 promoter (PEG-Prom) to drive E1A/E1B viral gene expression and expression of mda-7/IL-24 as a function of virus replication uniquely in prostate cancer cells. Specific Aim 3: Evaluate pre-clinical utility of conditionally replicating adenoviruses(CRAds) and infectivity enhanced conditionally replicating adenoviruses (IE-CRAds)(complex mosaic) in the context of a metastatic prostate cancer model in athymic nude mice. In summary, the proposed studies in this component of the program project will provide insights into the mechanism of action of a novel cancer specific apoptosis inducing cytokine, mda-7/IL-24, in the context of prostate cancer. Moreover, these experiments will provide a basis for future translational studies using this gene and its protein, alone or in combination with radiation, as an improved therapy for primary and metastatic prostate cancers.

尽管进行了深入的研究，但没有一种单一的治疗方法被证明能够非常成功地实现前列腺癌的长期治愈，即使疾病最初被检测为局部病灶。雄激素消融、前列腺切除术或放射治疗最多只能起到姑息作用，并对治疗后的生活质量产生严重影响。目前的统计数据表明，在根治性治疗干预后相对较短的时间内，复发频率很高，并伴有侵袭性转移。在传统治疗的生存获益有限的普遍情况下，基于基因治疗的方法代表了有希望的替代治疗前景。消减杂交鉴定出一种新基因——黑色素瘤 分化相关基因7。基于与 IL-10 的结构和功能同源性，mda-7 最近被重新命名为 IL-24。 mda-7/IL24 当通过无复制能力的腺病毒 Ad.mda-7 表达时，可通过诱导多种癌症（包括前列腺癌）的细胞凋亡来抑制生长并降低活力。相比之下， Ad.mda-7 不会对一系列正常细胞类型产生有害影响。这些观察结果已扩展到临床环境，表明 Ad.mda-7 是安全的，对晚期癌症和黑色素瘤患者进行单次瘤内注射可导致高比例 (> 70%) 的肿瘤细胞凋亡，并且重复剂量已产生客观的临床反应。正如 Ad.mda-7 所见，纯化的 GST-MDA-7 融合蛋白在应用于癌细胞（包括前列腺癌）时也会诱导细胞凋亡，但不适用于正常细胞。这些独特的癌症特异性细胞凋亡诱导特性表明，mda-7/IL-24 是一种强有力的候选癌症基因治疗剂，可用于治疗原发性前列腺肿瘤以及 转移。了解 mda-7/IL-24 诱导其抗前列腺癌特异性作用的机制将确定增强其活性、确定安全参数的方法，从而促进将该分子转移到临床治疗这种癌症的可能性。基于最近非常有希望的发现，将进行研究以： 具体目标 1：研究 mda-7/IL-24 前列腺癌特异性细胞凋亡诱导特性的基础。实验将通过诱变来定义结构/功能关系。鉴于 BCL-2 和 BCL-xL 在前列腺癌发展中的潜在核心作用，我们将确定它们在调节前列腺癌细胞对 mda 7/IL-24 敏感性中的重要性。我们将与 Dent 博士（项目 2）合作进行实验，以确定特定信号转导途径和电离辐射在调节 Ad.mda-7 蛋白介导的前列腺癌细胞凋亡诱导中的作用。具体目标 2：开发一种新颖、创新的基因治疗方法，增强 mda-8/IL-24 治疗前列腺癌的临床效用。 我们将与 Curiel 博士合作开发一种新型分类病毒。 （项目 3，CoreB）通过纤维/五邻体修饰（复杂嵌合体）改变感染性，使用进展性基因 3 启动子 (PEG-Prom) 驱动 E1A/E1B 病毒基因表达和前列腺癌特异性复制mda-7/IL-24 作为前列腺癌细胞中病毒复制的独特功能。具体目标 3：在无胸腺裸鼠的转移性前列腺癌模型中评估条件复制腺病毒 (CRAds) 和感染性增强的条件复制腺病毒 (IE-CRAds)（复合嵌合体）的临床前效用。总之，该计划项目这一部分的拟议研究将深入了解新型癌症特异性细胞凋亡诱导细胞因子 mda-7/IL-24 在前列腺癌中的作用机制。此外，这些实验将为未来使用该基因及其蛋白质单独或与放射组合作为原发性和转移性前列腺癌的改进疗法的转化研究提供基础。