Prostate cancer (PrCa) is one of the most heritable human cancers, as almost 60% of the PrCa risk is attributable to genetic factors. Inherited mutations in several genes involved in DNA damage response and repair (DDR) have been reported to predispose men to prostate cancer; this includes mutations in BRCA2, the genetic event known to confer the greatest risk of the disease. Recent studies have revealed that germline deleterious mutations in DDR genes are present in 8-12% of patients with metastatic PrCa, mutations in BRCA2 being the most prevalent ones. Our Group has previously established that these mutations are an independent prognostic factor for the disease. These observations have come full-circle with the development of Poly (ADP-ribose) polymerase inhibitors to treat advanced prostate cancer. Due to the high prevalence of DDR germline mutations and the implications for the patients and their families, clinical guidelines have recently been updated to recommend genetic screening to all patients with metastatic PrCa. In consequence, the number of mutation carriers is likely to grow over the next few years, whilst the most appropriate treatment and management still remains unknown. This year our Unit’s research has focussed on gaining a better understanding of the clinical implications of BRCA2 and other DDR defects ; the molecular characterisation of these tumours and the identification of biomarkers can enable us to predict the benefit derived from currently available therapies.
Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer(2018) Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ; SPARTAN Investigators. New Engl J Med 378, 1408-1418.
Patient-derived models of abiraterone and enzalutamide resistant prostate cancer reveal sensitivity to ribosome-directed therapy.(2018) Lawrence MG, Obinata D, Sandhu S, Selth LA, Wong SQ, Porter LH, Lister N, Pook D, Pezaro CJ, Goode DL, Rebello RJ, Clark AK, Papargiris M, Van Gramberg J, Hanson AR, Banks P, Wang H, Niranjan B, Keerthikumar S, Hedwards S, Huglo A, Yang R, Henzler C, Li Y, Lopez-Campos F, Castro E, Toivanen R, Azad A, Bolton D, Goad J, Grummet J, Harewood L, Kourambas J, Lawrentschuk N, Moon D, Murphy DG, Sengupta S, Snow R, Thorne H, Mitchell C, Pedersen J, Clouston D, Norden S, Ryan A, Dehm SM, Tilley WD, Pearson RB, Hannan RD, Frydenberg M, Furic L, Taylor RA, Risbridger GP Eur Urol 74, 562-572.
Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.(2018) Mikropoulos C, Selkirk CGH, Saya S, Bancroft E, Vertosick E, Dadaev T, Brendler C, Page E, Dias A, Evans DG, Rothwell J, Maehle L, Axcrona K, Richardson K, Eccles D, Jensen T, Osther PJ, van Asperen CJ, Vasen H, Kiemeney LA, Ringelberg J, Cybulski C, Wokolorczyk D, Hart R, Glover W, Lam J, Taylor L, Salinas M, Feliubadaló L, Oldenburg R, Cremers R, Verhaegh G, van Zelst-Stams WA, Oosterwijk JC, Cook J, Rosario DJ, Buys SS, Conner T, Domchek S, Powers J, Ausems MG, Teixeira MR, Maia S, Izatt L, Schmutzler R, Rhiem K, Foulkes WD, Boshari T, Davidson R, Ruijs M, Helderman-van den Enden AT, Andrews L, Walker L, Snape K, Henderson A, Jobson I, Lindeman GJ, Liljegren A, Harris M, Adank MA, Kirk J, Taylor A, Susman R, Chen-Shtoyerman R, Pachter N, Spigelman A, Side L, Zgajnar J, Mora J, Brewer C, Gadea N, Brady AF, Gallagher D, van Os T, Donaldson A, Stefansdottir V, Barwell J, James PA, Murphy D, Friedman E, Nicolai N, Greenhalgh L, Obeid E, Murthy V, Copakova L, McGrath J, Teo SH, Strom S, Kast K, Leongamornlert DA, Chamberlain A, Pope J, Newlin AC, Aaronson N, Ardern-Jones A, Bangma C, Castro E, Dearnaley D, Eyfjord J, Falconer A, Foster CS, Gronberg H, Hamdy FC, Johannsson O, Khoo V, Lubinski J, Grindedal EM, McKinley J, Shackleton K, Mitra AV, Moynihan C, Rennert G, Suri M, Tricker K; IMPACT study collaborators, Moss S, Kote-Jarai Z, Vickers A, Lilja H, Helfand BT, Eeles RA. Br J Cancer 118, 266-276.
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.(2017) Zabala-Letona A, Arruabarrena-Aristorena A, Martín-Martín N, Fernandez-Ruiz S, Sutherland JD, Clasquin M, Tomas-Cortazar J, Jimenez J, Torres I, Quang P, Ximenez-Embun P, Bago R, Ugalde-Olano A, Loizaga-Iriarte A, Lacasa-Viscasillas I, Unda M, Torrano V, Cabrera D, van Liempd SM, Cendon Y, Castro E, Murray S, Revandkar A, Alimonti A, Zhang Y, Barnett A, Lein G, Pirman D, Cortazar AR, Arreal L, Prudkin L, Astobiza I, Valcarcel-Jimenez L, Zuñiga-García P, Fernandez-Dominguez I, Piva M, Caro-Maldonado A, Sánchez-Mosquera P, Castillo-Martín M, Serra V, Beraza N, Gentilella A, Thomas G, Azkargorta M, Elortza F, Farràs R, Olmos D, Efeyan A, Anguita J, Muñoz J, Falcón-Pérez JM, Barrio R, Macarulla T, Mato JM, Martinez-Chantar ML, Cordon-Cardo C, Aransay AM, Marks K, Baselga J, Tabernero J, Nuciforo P, Manning BD, Marjon K, Carracedo A Nature 547, 109-113.
Anti-tumour activity in RAS-driven tumours by blocking AKT and MEK.(2015) Tolcher AW, Khan K, Ong M, Banerji U, Papadimitrakopoulou V, Gandara DR, Patnaik A, Baird RD, Olmos D, Garrett CR, Skolnik JM, Rubin EH, Smith PD, Huang P, Learoyd M, Shannon KA, Morosky A, Tetteh E, Jou YM, Papadopoulos KP, Moreno V, Kaiser B, Yap TA, Yan L, de Bono JS Clin Cancer Res 21, 739-748.
New advances in genitourinary cancer: evidence gathered in 2014.(2015) Suárez C, Puente J, Gallardo E, Méndez-Vidal MJ, Climent MA, León L, Olmos D7, García del Muro X, González-Billalabeitia E, Grande E, Bellmunt J, Mellado B, Maroto P, González del Alba A Cancer Metast Rev 34, 443-464.
Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis and poor survival outcomes in prostate cancer.(2013) Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, Mahmud N, Dadaev T, Govindasami K, Guy M, Sawyer E, Wilkinson R, Audern-Jones A, UKGPCS, Ellis S, Frost D, Peock S, Evans G, Tischkowitz M, Cole T, Davidson R, Eccles D, Brewer C, Douglas F, Porteous M, Donaldson A, Dorkins H, Izatt L, Cook J, Hodgson S, Kennedy J, Side L, Eason J, Murray A, Antonis A, Easton D, Kote-Jarai Z, Eeles R J Clin Oncol 31, 1748-1757.
