| Project title |
Identifying non-coding RNA repertoires of aggressive Prostate cancer |
| Summary |
Abstract:
Although there has been significant progress in the basic understanding of why prostate cancer (PCa) arises and how it progresses, these advances, unfortunately, have not translated into a cure and have most often have been disappointing with little benefit to men with aggressive PCa. Clinically relevant biomarkers are lacking and simple prognostication in PCa remains elusive outside of the now decades old pathological Gleason scoring system. Our hypothesis, supported by miRNA data from our laboratories, is that non-coding RNA signatures (including known and novel miRNAs) play a key role in aggressive PCa. In addition, cancer stemness is associated with poor prognosis and aggressive PCa. Therefore, we further hypothesize that non-coding RNA expression profiles, particularly miRNA, are linked to stemness in cancer and a clinically aggressive phenotype.
In this application, we aim to model stem cell rich PCa and profile biologically aggressive PCa (high Gleason grade) to identify, in hypothesis neutral experiments, non-coding RNAs associated with aggressive and progressive prostate cancer. miRNAs and their isoMirs will be defined in our holoclone stem cell models and high Gleason score tumours, from the biorepository of the Prostate Cancer Research Consortium (PCRC) in Ireland, and compared to founder cells and indolent prostate cancer respectively. Using advanced bioinformatics we will look for stemness and aggression signatures and use these in a smaller focused panel to assess in relation to outcome in richly and meticulously annotated prostate cancer databases from the Physicians Health Study and Health Professionals Follow Up Study. This study will also uniquely identify ncRNA other than miRNA (piRNA, snoRNA, transcribed ultra-conserved regions) and we expect that these will also contribute to the signatures derived. This study will for the first time provide an in depth profile of isoMirs in prostate cancer. We will also integrate existing and newly undertaken gene expression profiles to examine ncRNA in relation to gene expression patterns and pathways with the aim of deriving integrated ncRNA and mRNA profiles in clinically aggressive PCa.
Validation will be performed in independent cohorts and in databases of our collaborators in the United States (Harvard School of Public Health). The latter resource allows us to assess outcome in relation to Prostate cancer specific death rather than PSA failure and is annotated for protein pathway, gene expression profiling and clinical data. Aggressive disease in the Harvard datasets is characterized by the presence of metastases or death from PCa.
Finally, in a proof of concept study, we will examine the utility of the profiles discovered to monitor disease progression in circulating tumour cells from patients with aggressive metastatic prostate cancer. With the emergence of ncRNA-based therapeutics there is clear translational potential. The ultimate aim is to translate to the clinic non-coding RNA profiles that can be used to inform treatment options for patients with aggressive prostate cancer.
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| Funding Agency |
Prostate Cancer Foundation |
| Programme |
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| Type of Project |
Personal Fellowship |
| Date from |
01/01/12 |
| Date to |
30/12/14 |
| Person Months |
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Nguyen PL, Ma J, Chavarro JE, Freedman ML, Lis R, Fedele G, Fiore C, Qiu W, Fiorentino M, Finn S, Penney KL, Eisenstein A, Schumacher FR, Mucci LA, Stampfer MJ, Giovannucci E, Loda M, Fatty acid synthase polymorphisms, tumor expression, body mass index, prostate cancer risk, and survival., Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 28, (25), 2010, p3958-64
Url TARA - Full Text
DOI |
| Meyer MS, Penney KL, Stark JR, Schumacher FR, Sesso HD, Loda M, Fiorentino M, Finn S, Flavin RJ, Kurth T, Price AL, Giovannucci EL, Fall K, Stampfer MJ, Ma J, Mucci LA, Genetic variation in RNASEL associated with prostate cancer risk and progression., Carcinogenesis, 31, (9), 2010, p1597-603 |
Nucera C, Porrello A, Antonello ZA, Mekel M, Nehs MA, Giordano TJ, Gerald D, Benjamin LE, Priolo C, Puxeddu E, Finn S, Jarzab B, Hodin RA, Pontecorvi A, Nose V, Lawler J, Parangi S, B-Raf(V600E) and thrombospondin-1 promote thyroid cancer progression., Proceedings of the National Academy of Sciences of the United States of America, 107, (23), 2010, p10649-54
Url TARA - Full Text
DOI |
| Fiorentino M, Judson G, Penney K, Flavin R, Stark J, Fiore C, Fall K, Martin N, Ma J, Sinnott J, Giovannucci E, Stampfer M, Sesso HD, Kantoff PW, Finn S, Loda M, Mucci L, Immunohistochemical expression of BRCA1 and lethal prostate cancer., Cancer research, 70, (8), 2010, p3136-9 |
Flavin R, Smyth P, Barrett C, Russell S, Wen H, Wei J, Laios A, O'Toole S, Ring M, Denning K, Li J, Aherne S, Sammarae D, Aziz NA, Alhadi A, Finn SP, Loda M, B S, Sheils O, O'Leary JJ, miR-29b expression is associated with disease-free survival in patients with ovarian serous carcinoma., International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 19, (4), 2009, p641-7
DOI |
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