The role of placental gene PEG10 during transdifferenciation into neuroendocrine prostatecancer

胎盘基因PEG10在神经内分泌前列腺癌转分化过程中的作用

• 批准号: 269895856
• 负责人: Dr. Alexander Kretschmer
• 金额: --
• 依托单位: Prostate Centre
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/269895856?language=en
• 关键词: role; placental; gene; PEG10; during

Prostate cancer is the most common solid organ malignancy in the western world and its growth is highly androgen-driven. Advanced prostate cancer is regularly treated via androgen deprivation therapy. Unfortunately, most patients progress to so-called castration-resistant prostate cancer (CRPC). In this state, classic anti-androgens and gonadotropin-releasing hormone inhibitors fail to sufficiently inhibit tumor cell growth. Amongst the CRPC, the neuroendocrine prostate cancer (NEPC) is one of the most recognized one. NEPC is highly metastatic and lethal, and currently without effective treatment. Therefore, a novel therapeutic approach to treat NEPC is urgently needed. Using a recently developed first-in-field patient-derived xenograft model of NEPC transdifferentiation, the working group of Prof. M. Gleave recently identified retrotransposon-derived gene Paternally Expressed 10 (PEG10) to be highly expressed early post-castration and further up-regulated in NEPC. The impact of PEG10 on neuroendocrine transformation from adenocarcinoma of the prostate and its progression to NEPC has not been investigated until recently and it is still unclear if PEG10 up-regulation can be used as a potential therapeutic target in NEPC. To further elucidate this topic, we aim to functionally characterize PEG10 in NEPC and metastatic prostate cancer. In addition, we will study the impact of PEG10 up-regulation on prostate cancer phenotype, proliferation rates, apoptosis with respect to the respective cell cycle point, and cell invasion. In vivo and in vitro studies of potential regulators will also be included. Finally, a potential therapeutic use of PEG10 will be evaluated by identifying and creating an antisense oligonucleotide against PEG10 and elucidate its therapeutic potential in vitro as well as in vivo. In summary, the overall aim of my research proposal is to increase the knowledge about the role of PEG10 during transformation from adenocarcinoma to NEPC and its potential therapeutic use against a deadly disease.

前列腺癌是西方世界最常见的实体器官恶性肿瘤，其生长高度雄激素驱动。晚期前列腺癌通常通过雄激素剥夺疗法进行治疗。不幸的是，大多数患者进展为所谓的去势抵抗性前列腺癌（CRPC）。在这种状态下，经典的抗雄激素和促性腺激素释放激素抑制剂不能充分抑制肿瘤细胞生长。在CRPC中，神经内分泌前列腺癌（NEPC）是最受认可的癌症之一。NEPC具有高度转移性和致死性，目前尚无有效的治疗方法。因此，迫切需要一种新的治疗NEPC的方法。使用最近开发的第一个在现场的患者来源的NEPC转分化异种移植模型，M。Gleave最近发现逆转录转座子衍生的基因父系表达10（PEG10）在去势后早期高度表达，并在NEPC中进一步上调。PEG10对前列腺腺癌神经内分泌转化及其进展为NEPC的影响直到最近才被研究，目前尚不清楚PEG10上调是否可用作NEPC的潜在治疗靶点。为了进一步阐明这一主题，我们的目标是PEG10在NEPC和转移性前列腺癌中的功能特征。此外，我们将研究PEG10上调对前列腺癌表型、增殖率、细胞凋亡（相对于各自的细胞周期点）和细胞侵袭的影响。还将包括潜在调节剂的体内和体外研究。最后，将通过鉴定和创建针对PEG10的反义寡核苷酸来评估PEG10的潜在治疗用途，并阐明其体外和体内的治疗潜力。总之，我的研究提案的总体目标是增加对PEG10在从腺癌向NEPC转化过程中的作用及其对致命疾病的潜在治疗用途的了解。

项目成果

Paternally Expressed Gene 10 (PEG10) Promotes Growth, Invasion, and Survival of Bladder Cancer

• DOI: 10.1158/1535-7163.mct-19-1031
• 发表时间: 2020-10-01
• 期刊: MOLECULAR CANCER THERAPEUTICS
• 影响因子: 5.7
• 作者: Kawai, Yoshihisa;Imada, Kenjiro;Gleave, Martin E.
• 通讯作者: Gleave, Martin E.

Characterizing androgen receptor blockade- and metabolic stress-induced tunneling nanotube formation supporting stress adaptivity in prostate cancer

表征雄激素受体阻断和代谢应激诱导的隧道纳米管形成，支持前列腺癌的应激适应性

• DOI: 10.1016/s1569-9056(17)30218-x
• 发表时间: 2017
• 期刊: European Urology Supplements
• 作者: Alexander Kretschmer;Fan Zhang;Syam Prakash Somasekharan;Charan Tse;Lauren Leachman;Anna Gleave;Brian Li;Ivan Asmaro;Poul H. Sorensen;Martin E. Gleave
• 通讯作者: Martin E. Gleave

Stress-induced tunneling nanotubes support treatment adaptation in prostate cancer

• DOI: 10.1038/s41598-019-44346-5
• 发表时间: 2019-05-24
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Kretschmer, Alexander;Zhang, Fan;Gleave, Martin E.
• 通讯作者: Gleave, Martin E.