Adenovirus E1B55K Functions Related to Oncolytic Replication

腺病毒 E1B55K 与溶瘤复制相关的功能

基本信息

批准号：
8207278
负责人：
Heshan Sam ZHOU
金额：
$ 26.81万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2014-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Two major "hallmarks" of all cancer cells include dysregulated cell cycle and inhibited apoptosis, both of which are also involved in adenovirus (Ad) infection. These two processes are primarily conducted by viral oncoproteins E1A and E1B. Since the function of viral E1 protein is similar to that of cancer cellular factors that promote proliferation and inhibit apoptosis, viruses with mutations in oncoprotein E1A and E1B can selectively replicate in cancer cells. One such mutant with deletion of E1B55K, known as dl1520, has been used in clinical trials documenting oncolytic effects. However, the mechanism of viral oncolytic replication has not been well characterized, and the therapeutic efficacy needs improvement. It is generally believed that the major role of E1B55K is to bind to and inhibit p53 activation, but many studies have documented that E1B55K-mediated p53 inactivation is not required for virus replication. Our laboratory has shown: (1) that the limited spread of mutant viruses in large tumors is a key factor in decreased therapeutic efficacy; (2) increased Ad E1A expression enhances virus-oncolytic replication; and (3) apoptosis caused by E1B deletion can partially decrease virus replication but does not change the final outcome of virus-mediated cancer killing. Our recent studies have revealed that E1B55K has a novel function in the induction of cyclin E and other cell cycle-related genes. Most importantly, we also observed that increased cyclin E expression is correlated with virus replication efficiency. E1B55K-induced cyclin E expression is required for virus replication in normal cells, but is not necessary in cancer cells. We hypothesize that E1B55K may target cellular factor(s) to increase cyclin E expression, and this factor(s) may already be activated in cancer cells. Thus, cyclin E dysregulation in cancer cells may be the molecular basis for oncolytic replication of E1B55K-deleted viruses. Our research team will (1) identify cellular factors targeted by E1B55K for cyclin E induction, (2) define the mechanism by which E1B55K activates cyclin E expression, and (3) determine the relationship between cyclin E overexpression and oncolytic replication of E1B-deleted viriuses. If we confirm that oncolytic replication relies on cyclin E expression and cell proliferation, patients with aggressively growing tumors and dysregulated cyclin E should greatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy of oncolytic cancer gene therapy. PUBLIC HEALTH RELEVANCE: Adenoviruses lacking an important regulative protein-E1B55K-still can amplify in some cancer cells. Therefore, the E1B55K mutant dl1520 has been used in clinical trials. It is important to understand the E1B55K function and the selective replication of E1B55K-deleted dl1520 in cancer cells. Our recently published studies have revealed that E1B55K has a novel function in the induction of cyclin E expression, which is crucial for DNA replication. Cancer cells generally express high levels of cyclin E or have a dysregulation of the gene. We reason that viral E1B55K may activate some cellular factors that increase cyclin E expression for viral DNA replication. Cancer cells may already have the factors activated; therefore cancer cells do not require the E1B55K function. The study of this possibility is very important. If we confirm that mutated virus replication relies on cyclin E expression, patients with aggressively growing tumors and dysregulated cyclin E should greatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy of oncolytic cancer gene therapy.

描述（由申请人提供）：所有癌细胞的两个主要“标志”包括细胞周期失调和细胞凋亡受抑制，这两者也与腺病毒（Ad）感染有关。这两个过程主要由病毒癌蛋白 E1A 和 E1B 进行。由于病毒E1蛋白的功能与促进增殖、抑制凋亡的癌细胞因子相似，因此癌蛋白E1A和E1B突变的病毒可以在癌细胞中选择性复制。一种删除了 E1B55K 的突变体（称为 dl1520）已用于记录溶瘤效应的临床试验。然而，病毒溶瘤复制的机制尚未得到很好的表征，治疗效果有待提高。人们普遍认为E1B55K的主要作用是结合并抑制p53激活，但许多研究证明病毒复制不需要E1B55K介导的p53失活。我们实验室已经证明：（1）突变病毒在大肿瘤中有限的传播是治疗效果下降的关键因素； (2) Ad E1A表达增加增强病毒溶瘤复制； (3)E1B缺失引起的细胞凋亡可以部分减少病毒复制，但不会改变病毒介导的癌症杀伤的最终结果。我们最近的研究表明，E1B55K 在诱导细胞周期蛋白 E 和其他细胞周期相关基因方面具有新的功能。最重要的是，我们还观察到细胞周期蛋白 E 表达的增加与病毒复制效率相关。 E1B55K 诱导的细胞周期蛋白 E 表达是病毒在正常细胞中复制所必需的，但在癌细胞中则不是必需的。我们假设 E1B55K 可能靶向细胞因子以增加细胞周期蛋白 E 的表达，并且该因子可能已经在癌细胞中被激活。因此，癌细胞中的细胞周期蛋白 E 失调可能是 E1B55K 缺失病毒溶瘤复制的分子基础。我们的研究团队将 (1) 识别 E1B55K 诱导细胞周期蛋白 E 所靶向的细胞因子，(2) 确定 E1B55K 激活细胞周期蛋白 E 表达的机制，以及 (3) 确定细胞周期蛋白 E 过表达与 E1B 缺失的溶瘤复制之间的关系病毒。如果我们确认溶瘤复制依赖于细胞周期蛋白 E 表达和细胞增殖，那么肿瘤生长迅速且细胞周期蛋白 E 失调的患者应该会从这种腺病毒治疗中受益匪浅。这项工作的长期目标是提高溶瘤癌症基因治疗的功效。公共健康相关性：缺乏重要调节蛋白 E1B55K 的腺病毒仍然可以在某些癌细胞中扩增。因此，E1B55K突变体dl1520已用于临床试验。了解 E1B55K 功能以及 E1B55K 缺失的 dl1520 在癌细胞中的选择性复制非常重要。我们最近发表的研究表明，E1B55K 在诱导细胞周期蛋白 E 表达方面具有新功能，这对于 DNA 复制至关重要。癌细胞通常表达高水平的细胞周期蛋白 E 或该基因失调。我们推断病毒 E1B55K 可能会激活一些细胞因子，从而增加细胞周期蛋白 E 的表达以促进病毒 DNA 复制。癌细胞可能已经激活了这些因子；因此癌细胞不需要E1B55K功能。研究这种可能性非常重要。如果我们确认突变病毒的复制依赖于细胞周期蛋白 E 的表达，那么肿瘤生长迅速且细胞周期蛋白 E 失调的患者应该会从这种腺病毒治疗中受益匪浅。这项工作的长期目标是提高溶瘤癌症基因治疗的功效。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adenoviruses induce autophagy to promote virus replication and oncolysis.

DOI：
10.1016/j.virol.2011.04.017
发表时间：
2011-07-20
期刊：
Virology
影响因子：
3.7
作者：
Rodriguez-Rocha H;Gomez-Gutierrez JG;Garcia-Garcia A;Rao XM;Chen L;McMasters KM;Zhou HS
通讯作者：
Zhou HS

Oncolytic adenovirus targeting cyclin E overexpression repressed tumor growth in syngeneic immunocompetent mice.

DOI：
10.1186/s12885-015-1731-x
发表时间：
2015-10-16
期刊：
BMC cancer
影响因子：
3.8
作者：
Cheng PH;Rao XM;Wechman SL;Li XF;McMasters KM;Zhou HS
通讯作者：
Zhou HS

Combination of autophagy inducer rapamycin and oncolytic adenovirus improves antitumor effect in cancer cells.

DOI：
10.1186/1743-422x-10-293
发表时间：
2013-09-23
期刊：
Virology journal
影响因子：
4.8
作者：
Cheng PH;Lian S;Zhao R;Rao XM;McMasters KM;Zhou HS
通讯作者：
Zhou HS

Combined therapy of oncolytic adenovirus and temozolomide enhances lung cancer virotherapy in vitro and in vivo.

DOI：
10.1016/j.virol.2015.10.019
发表时间：
2016-01
期刊：
Virology
影响因子：
3.7
作者：
Gomez-Gutierrez JG;Nitz J;Sharma R;Wechman SL;Riedinger E;Martinez-Jaramillo E;Sam Zhou H;McMasters KM
通讯作者：
McMasters KM

Oncolytic Replication of E1b-Deleted Adenoviruses.