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: 7470277
• 负责人: Santanu Bose
• 金额: $ 16.65万
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470277
• 关键词: Ablation; Accounting; Age; Aging; Androgens; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Antiviral Response; Apoptosis; Appendix; Cancer Etiology; Cells; Cellular biology; Cessation of life; Child; Class; Clinical Trials; Data; Defect; Disease; Disease regression; Elderly; Elderly man; Epithelial Cells; Family; Family member; Histology; Human respiratory syncytial virus; In Situ; In Vitro; Infant; Infection; Interferon Type I; Interferons; Interleukin-1; Life; Lung diseases; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Modeling; Natural Immunity; Normal Cell; Nude Mice; Oncolytic; Oncolytic viruses; Other Body Part; Paramyxovirus; Pathway interactions; Phase; Population; Property; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Public Health; RNA Viruses; Radiation therapy; Rate; Relapse; Reporting; Respiratory System; Respiratory syncytial virus; Role; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Standards of Weights and Measures; Subfamily lentivirinae; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Viral; Viral Load result; Virus; Virus Diseases; base; bone; cancer cell; cancer risk; cancer therapy; chemotherapy; chromatin immunoprecipitation; cytokine; design; disorder control; disorder risk; gene induction; human TNF protein; in vivo; killings; knock-down; male; men; mortality; mouse model; neoplastic cell; novel; oncolysis; paracrine; response; success; tool; tumor; tumor xenograft; tumorigenic

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，其侵略性形式将扩散到骨骼和人体的许多其他部位。男性老龄化尤其容易患这种疾病，因为从生命的第五个十年开始，前列腺癌的风险稳定增长。实际上，70岁以上男性实体瘤的新病例约为60％，代表了前列腺中的肿瘤。转移性前列腺癌是老年男性癌症死亡的主要原因。拟议的研究有望提供有关该策略来管理前列腺癌策略的新信息，以选择性杀死前列腺肿瘤细胞的肿瘤人呼吸道综合病毒（RSV）。溶瘤病毒疗法是一个新兴的生物治疗平台，用于癌症治疗，该平台基于选择性感染和癌细胞的“杀死”。迄今为止，已经确定了八种溶瘤病毒。但是，最近的临床试验表明，需要采用多病毒病毒疗法的方法来治疗侵袭性癌症，因此需要鉴定新型溶瘤病毒的紧迫性。为此，我们已经将RSV确定为一种新型的溶瘤病毒，因为RSV具有针对前列腺肿瘤细胞的有效抗癌活性。我们的结果表明，与非肿瘤性RWPE-1人类前列腺细胞相比，我们对雄激素不敏感的，高度转移的PC-3人前列腺癌细胞的RSV感染性急剧增强。 PC-3细胞中的病毒负担增强导致在体外和人体内的PC-3癌细胞的选择性“杀死”，在裸鼠中生长的人体前列腺肿瘤异种移植物。我们进一步证明，RSV的溶瘤功能的基础机制涉及PC-3细胞中依赖性的先天性抗病毒反应中的缺陷。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细胞中有功能障碍的先天反应导致病毒感染性和肿瘤分解增加。拟议的研究将以两个具体的目的进行：目标1）表征RSV介导的肿瘤异种移植物体内前列腺癌细胞的术和前列腺癌的流浪小鼠模型。目的2）研究失控的NF-？B依赖性抗病毒途径在将前列腺癌细胞中的RSV赋予RSV方面的作用。 RSV介导的体内肿瘤分解将根据肿瘤回归评估；前列腺组织学；原位凋亡； PC-3细胞在荧光原位模型中的转移扩散。通过慢病毒介导的siRNA表达和染色质免疫沉淀，将使用细胞生物学方法（包括击倒特定的NF-？b家族成员）的细胞生物学方法来探索失控的NF-？B功能。意义：RSV的溶瘤特性可以作为一种有效的治疗工具来特异性靶向前列腺肿瘤。公共卫生相关性：前列腺癌是老年人群死亡的主要原因，而新颖的抗癌治疗对于控制这种疾病是必要的。我们已经确定呼吸综合病毒是一种新型的抗癌剂，可以选择性地破坏前列腺癌细胞，而不是正常细胞。因此，该病毒可用于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。