The role of placental gene PEG10 during transdifferenciation into neuroendocrine prostatecancer

前列腺癌是西方世界最常见的实体器官恶性肿瘤，其生长高度受雄激素驱动。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，大多数患者会发展成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的生长。在CRPC中，神经内分泌前列腺癌（NEPC）是最被认可的一类。NEPC是高度转移和致命的，目前没有有效的治疗方法。因此，迫切需要一种新的治疗方法来治疗NEPC。M. Gleave教授的工作小组利用最近首次开发的患者来源的NEPC转分化异种移植模型，最近发现逆转录转座子来源的基因父系表达10 （PEG10）在阉割后早期高表达，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向NEPC进展的影响直到最近才被研究，PEG10上调是否可以作为NEPC的潜在治疗靶点尚不清楚。为了进一步阐明这一主题，我们的目标是功能表征PEG10在NEPC和转移性前列腺癌中的作用。此外，我们将研究PEG10上调对前列腺癌表型、增殖率、细胞周期点凋亡和细胞侵袭的影响。还将包括潜在调节因子的体内和体外研究。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，并阐明其在体外和体内的治疗潜力。综上所述，我的研究计划的总体目标是增加对PEG10在腺癌向NEPC转化过程中的作用的了解，以及它对致命疾病的潜在治疗用途。

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.