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。老年男性尤其容易患上这种疾病，因为从生命的第五个十年开始，前列腺癌的风险稳步上升。事实上，在70岁以上的男性中，约60%的实体瘤新发病例代表前列腺肿瘤。转移性前列腺癌是老年男性癌症死亡的主要原因。这项拟议的研究预计将提供新的信息的战略，以管理前列腺癌的基础上选择性杀死前列腺肿瘤细胞的溶瘤人呼吸道合胞病毒（RSV）。溶瘤病毒治疗是一种新兴的肿瘤生物治疗平台，其基于选择性感染和“杀死”癌细胞。迄今为止，已鉴定出8种溶瘤病毒。然而，最近的临床试验表明，需要一种多病毒的病毒治疗方法来治疗侵袭性癌症，因此，迫切需要确定新的溶瘤病毒。为此，我们已经将RSV鉴定为新型溶瘤病毒，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，雄激素不敏感的高转移性PC-3人前列腺癌细胞中RSV感染性显著增强。PC-3细胞中增强的病毒负荷导致在裸鼠中生长的人前列腺肿瘤异种移植物中体外和体内选择性“杀死”PC-3癌细胞。我们进一步证明，RSV的溶瘤功能的可能机制涉及NF-？PC-3细胞中的B依赖性先天性抗病毒应答。由于抗病毒先天免疫构成了限制病毒感染的第一道防线，我们推测PC-3细胞中功能失调的先天性应答是导致病毒感染性和溶瘤性增加的原因。所提出的研究将以两个特定目的进行：目的1）表征肿瘤异种移植物和前列腺癌TRAMP小鼠模型中体内RSV介导的前列腺癌细胞溶瘤作用。目的2）研究NF-？B依赖性抗病毒途径在前列腺癌细胞中赋予RSV溶瘤功能。将根据肿瘤消退、前列腺组织学、原位细胞凋亡和荧光原位模型中PC-3细胞的转移扩散评估RSV介导的体内溶瘤作用。解除管制的NF-？B功能将探讨使用细胞生物学方法，包括敲低特定的NF-？B家族成员通过慢病毒介导的siRNA表达和染色质免疫沉淀。意义：RSV的溶瘤特性可被开发为特异性靶向前列腺肿瘤的有效治疗工具。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作为一种新型抗癌剂，可以选择性地破坏前列腺癌细胞，但不是正常细胞。因此，该病毒可用作治疗剂，以设计安全有效的基于病毒的抗癌剂，以特异性靶向前列腺肿瘤。