Dr Mark Hintze

Neuroendocrine Prostate Cancer (NEPC) is an incurable disease, which originates from the trans-differentiation of prostatic adenocarcinomas exposed to prolonged hormonal therapies (1). NEPC is incurable, with a median survival shorter than 1 year. NEPC pathogenesis is largely unknown. This is due to the lack of suitable pre-clinical models for this disease. We have recently replicated a technique that allows us to transform prostate adenocarcinoma cells into NEPC cells by hypoxia conditioning (2). We propose to use this technique to develop and characterise new NEPC models, which will be then used to identify new therapeutic targets for NEPC. We would like to receive expressions of interest from a range of PhD candidates working on this project with potential industrial collaborators (part-time or full-time, depending on mutual agreement). The main aims of the project will be: 1. To generate and characterise NEPC cells by hypoxia conditioning 2. To identify genes that are differentially expressed between NEPC and non-NEPC cells 3. To test whether any of these differentially expressed genes is a promising therapeutic target for NEPC. The project will be co-created with the successful candidate. Hence, the candidate is encouraged to consider techniques that could be used to identify new therapeutic targets, referring to previous publications from our laboratory (3-5). These techniques may include innovative bioinformatic tools (e.g. analysis of RNA Seq data from patient datasets). This part of the project will be supervised by Dr Hintze, who has specific expertise in bioinformatic analyses. The final aim of this project is to generate new NEPC models, and to identify at least one new therapeutic target for this incurable disease. References 1. Wang Y, Wang Y, Ci X, Choi SYC, Crea F, Lin D, Wang Y. Molecular events in neuroendocrine prostate cancer development. Nat Rev Urol. 2021 Oct;18(10):581-596. doi: 10.1038/s41585-021-00490-0. Epub 2021 Jul 21. PMID: 34290447; PMCID: PMC10802813. 2. Danza G, Di Serio C, Rosati F, Lonetto G, Sturli N, Kacer D, Pennella A, Ventimiglia G, Barucci R, Piscazzi A, Prudovsky I, Landriscina M, Marchionni N, Tarantini F. Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells. Mol Cancer Res. 2012 Feb;10(2):230-8. doi: 10.1158/1541-7786.MCR-11-0296. Epub 2011 Dec 15. PMID: 22172337; PMCID: PMC3433043. 3. Wang Y, Xue H, Zhu X, Lin D, Dong X, Chen Z, Chen J, Shi M, Ni Y, Cao J, Wu R, Kang N, Pang X, Crea F, Lin YY, Collins CC, Gleave ME, Parolia A, Chinnaiyan A, Ong CJ, Wang Y. Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation. bioRxiv [Preprint]. 2024 Apr 29:2024.04.27.591428. doi: 10.1101/2024.04.27.591428. PMID: 38746377; PMCID: PMC11092479. 4. Mather RL, Parolia A, Carson SE, Venalainen E, Roig-Carles D, Jaber M, Chu SC, Alborelli I, Wu R, Lin D, Nabavi N, Jachetti E, Colombo MP, Xue H, Pucci P, Ci X, Hawkes C, Li Y, Pandha H, Ulitsky I, Marconett C, Quagliata L, Jiang W, Romero I, Wang Y, Crea F. The evolutionarily conserved long non-coding RNA LINC00261 drives neuroendocrine prostate cancer proliferation and metastasis via distinct nuclear and cytoplasmic mechanisms. Mol Oncol. 2021 Jul;15(7):1921-1941. doi: 10.1002/1878-0261.12954. Epub 2021 Apr 26. PMID: 33793068; PMCID: PMC8253100. 5. Silvestri R, Pucci P, Venalainen E, Matheou C, Mather R, Chandler S, Aceto R, Rigas SH, Wang Y, Rietdorf K, Bootman MD, Crea F. T-type calcium channels drive the proliferation of androgen-receptor negative prostate cancer cells. Prostate. 2019 Sep;79(13):1580-1586. doi: 10.1002/pros.23879. Epub 2019 Jul 23. PMID: 31334879.