Oncolytic activity of respiratory syncytial virus against prostate cancer

描述(申请人提供)：前列腺癌是一种恶性肿瘤，以其侵袭性的形式会扩散到骨骼和身体的许多其他部位。老年男性人口特别容易患这种疾病，因为从第五个十年开始，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%的实体肿瘤新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。这项拟议的研究有望为基于溶瘤的人类呼吸道合胞病毒(RSV)选择性杀伤前列腺癌细胞的前列腺癌管理策略提供新的信息。溶瘤病毒治疗是一种新兴的肿瘤治疗生物治疗平台，其基础是选择性感染和杀伤癌细胞。到目前为止，已鉴定出8种溶瘤病毒。然而，最近的临床试验表明，需要一种多病毒病毒疗法来治疗侵袭性癌症，因此迫切需要识别新的溶瘤病毒。为此，我们将RSV鉴定为一种新的溶瘤病毒，因为RSV对前列腺肿瘤细胞具有强大的抗癌活性。我们的结果表明，与非致瘤的RWPE-1人前列腺癌细胞相比，雄激素不敏感、高转移的PC-3人前列腺癌细胞中RSV的传染性显著增强。PC-3细胞中病毒载量的增加导致在裸鼠体内生长的人前列腺癌异种移植瘤中，PC-3癌细胞在体外和体内都被选择性地杀死。我们进一步证明了RSV溶瘤功能的可能机制涉及PC-3细胞中依赖于核因子？B的先天抗病毒反应的缺陷。由于抗病毒先天免疫是限制病毒感染的第一道防线，我们推测PC-3细胞的先天免疫功能障碍是导致病毒感染性增加和溶瘤的原因。这项拟议的研究将有两个特定的目的：目的1)研究RSV介导的前列腺癌细胞在体内异种移植瘤和前列腺癌TRAMP小鼠模型中的溶瘤作用。目的2)研究去调节的核因子？B依赖的抗病毒途径在前列腺癌细胞中对RSV的溶瘤作用。RSV介导的体内溶瘤作用将基于肿瘤消退、前列腺组织学、原位凋亡和PC-3细胞在荧光原位模型中的转移扩散进行评估。通过慢病毒介导的siRNA表达和染色质免疫沉淀等细胞生物学方法，研究去调节的核转录因子？B的功能。意义：RSV的溶瘤特性可被开发为一种有效的治疗工具来特异性地靶向前列腺癌。公共卫生相关性：前列腺癌是老年人口死亡的主要原因，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的抗癌药物，可以选择性地摧毁前列腺癌细胞，但不能摧毁正常细胞。因此，该病毒可以作为一种治疗性药物来设计安全有效的针对前列腺癌的基于病毒的抗癌药物。

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.