Oncolytic activity of respiratory syncytial virus against prostate cancer

呼吸道合胞病毒对前列腺癌的溶瘤活性

• 批准号: 7564763
• 负责人: Santanu Bose
• 金额: $ 20.03万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564763
• 关键词: A549; Age; Aging; Androgens; Animals; Antineoplastic Agents; Antiviral Agents; Antiviral Response; Apoptosis; Attenuated; Biological Assay; Body part; Breast; C57BL/6 Mouse; Cancer Etiology; Cell Line; Cell Nucleus; Cells; Cellular biology; Cessation of life; Clinical Trials; Colon Carcinoma; Critiques; DU145; Data; Data Analyses; Defect; Disease; Distal; Dose; Down-Regulation; Elderly; Elderly man; Epithelial Cells; Evaluation; Family member; Feedback; Figs - dietary; Future; Gene Expression; Histology; Homing; Human; Human respiratory syncytial virus; Image; In Situ; In Vitro; Infection; LAPC4; LNCaP; Life; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Metastatic Prostate Cancer; Modeling; Mucous Membrane; Mus; Names; Natural Immunity; Normal Cell; Nude Mice; Oncolytic; Oncolytic viruses; Organ; PC3 cell line; Pancreas; Pathway interactions; Population; Primary Neoplasm; Principal Investigator; Production; Property; Prostate; Prostatic Neoplasms; Proteins; Publications; Published Comment; Publishing; Reaction Time; Regulation; Reporting; Resources; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Role; Safety; Signal Transduction; Site; Small Interfering RNA; Solid Neoplasm; Subfamily lentivirinae; Systemic infection; TNF gene; Therapeutic; Vertebrates; Viral; Viral Genes; Viral Load result; Virulent; Virus; Virus Diseases; Virus Replication; Western Blotting; Xenograft procedure; base; bone; cancer cell; cancer risk; cancer therapy; cell killing; chromatin immunoprecipitation; cytokine; design; disorder control; in vivo; killings; knock-down; male; men; mortality; mouse model; neoplastic cell; nonhuman primate; novel; oncolysis; programs; public health relevance; research study; response; skeletal; tool; tumor; tumor specificity; tumor xenograft; tumorigenic; vector

DESCRIPTION (provided by applicant): Prostate cancer is a malignant tumor, which in its aggressive form would spread to the bone and many other parts of the body. The aging male population is especially susceptible to this disease, since from the 5th decade of life the prostate cancer risk rises steadily. In fact, ~ 60% new cases of solid tumors in men over age 70 represent tumors in the prostate gland. Metastatic prostate cancer is the leading cause of cancer deaths among elderly men. The proposed study is expected to provide novel information on the strategy to manage prostate cancer based on selective killing of prostate tumor cells by the oncolytic human respiratory syncytial virus (RSV). Oncolytic virotherapy is an emerging bio-therapeutic platform for cancer treatment, which is based on selective infection and "killing" of cancer cells. To date, eight oncolytic viruses have been identified. However, recent clinical trials indicated the need for a multi-virus virotherapy approach for the treatment of aggressive cancers and thus, the urgency to identify novel oncolytic viruses. To this end, we have identified RSV as a novel oncolytic virus, since RSV possesses potent anti-cancer activity against prostate tumor cells. Our results demonstrated dramatic enhancement of RSV infectivity in the androgen-insensitive, highly metastatic PC-3 human prostate cancer cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden in PC-3 cells leads to selective "killing" of PC-3 cancer cells in vitro and in vivo in human prostate tumor xenografts grown in nude mice. We further demonstrated that the possible mechanism underlying the oncolytic function of RSV involves defect in the NF-?B dependent innate anti-viral response in PC-3 cells. Since anti-viral innate immunity constitutes the first line of defense directed to restrict viral infection, we speculate that dysfunctional innate response in PC-3 cells is responsible for the increased viral infectivity and oncolysis. The proposed study will be pursued with two Specific Aims: Aim 1) Characterize the RSV-mediated oncolysis of prostate cancer cells in vivo in tumor xenografts and in the TRAMP mouse model of prostate cancer. Aim 2) Study the role of the deregulated NF-?B dependent anti-viral pathway in conferring the oncolytic function to RSV in prostate cancer cells. RSV-mediated oncolysis in vivo will be assessed based on tumor regression; prostate histology; apoptosis in situ; and metastatic spread of PC-3 cells in a fluorescent orthotopic model. Deregulated NF-?B function will be explored using cell biology approaches including knock down of specific NF-?B family members by lentivirus-mediated siRNA expression and chromatin immunoprecipitation. Significance: The oncolytic property of RSV could be developed as an efficient therapeutic tool to specifically target prostate tumors. PUBLIC HEALTH RELEVANCE: Prostate cancer is a leading cause of mortality among elderly population and novel anti-cancer treatment is necessary to control this disease. We have identified respiratory syncytial virus as a novel anti-cancer agent that could selectively destroy prostate cancer cells, but not normal cells. Therefore, this virus could be utilized as a therapeutic to design safe and efficient virus-based anti-cancer agents to specifically target prostate tumors.

描述（由申请人提供）：前列腺癌是一种恶性肿瘤，其侵袭性形式会扩散到骨骼和身体的许多其他部位。老年男性特别容易患这种疾病，因为从五岁开始，前列腺癌的风险稳步上升。事实上，70 岁以上男性中约 60% 的新实体瘤病例是前列腺肿瘤。转移性前列腺癌是老年男性癌症死亡的主要原因。拟议的研究有望为基于溶瘤人类呼吸道合胞病毒（RSV）选择性杀死前列腺肿瘤细胞的前列腺癌治疗策略提供新的信息。溶瘤病毒疗法是一种新兴的癌症治疗生物治疗平台，其基于选择性感染和“杀死”癌细胞。迄今为止，已鉴定出八种溶瘤病毒。然而，最近的临床试验表明需要一种多病毒病毒疗法来治疗侵袭性癌症，因此迫切需要鉴定新型溶瘤病毒。为此，我们将 RSV 确定为一种新型溶瘤病毒，因为 RSV 对前列腺肿瘤细胞具有有效的抗癌活性。我们的结果表明，与非致瘤性 RWPE-1 人前列腺细胞相比，雄激素不敏感、高度转移性 PC-3 人前列腺癌细胞中 RSV 感染性显着增强。 PC-3细胞中病毒负荷的增加导致在体外和体内在裸鼠中生长的人前列腺肿瘤异种移植物中选择性“杀死”PC-3癌细胞。我们进一步证明RSV溶瘤功能的可能机制涉及PC-3细胞中NF-κB依赖性先天抗病毒反应的缺陷。由于抗病毒先天免疫构成了限制病毒感染的第一道防线，因此我们推测 PC-3 细胞中功能失调的先天反应是病毒感染性和溶瘤作用增加的原因。拟议的研究将有两个具体目标： 目标 1) 在肿瘤异种移植物和前列腺癌 TRAMP 小鼠模型中表征体内 RSV 介导的前列腺癌细胞溶瘤作用。目标 2) 研究失调的 NF-κB 依赖性抗病毒途径在赋予前列腺癌细胞 RSV 溶瘤功能中的作用。 RSV介导的体内溶瘤作用将根据肿瘤消退进行评估；前列腺组织学；原位细胞凋亡；以及荧光原位模型中 PC-3 细胞的转移扩散。将使用细胞生物学方法探索失调的 NF-κB 功能，包括通过慢病毒介导的 siRNA 表达和染色质免疫沉淀敲低特定的 NF-κB 家族成员。意义：RSV 的溶瘤特性可开发为一种有效的治疗工具，专门针对前列腺肿瘤。公共卫生相关性：前列腺癌是老年人群死亡的主要原因，需要新的抗癌治疗来控制这种疾病。我们已经确定呼吸道合胞病毒是一种新型抗癌剂，可以选择性地破坏前列腺癌细胞，但不能破坏正常细胞。因此，这种病毒可以用作治疗剂，设计安全有效的基于病毒的抗癌剂，专门针对前列腺肿瘤。