The role of placental gene PEG10 during transdifferenciation into neuroendocrine prostate cancer

• Applicant: Dr. Alexander Kretschmer
• Subject Area: Reproductive Medicine, Urology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269895856

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.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Professor Dr. Martin Gleave