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  • 1 Semmelweis Egyetem, Általános Orvostudományi Kar, Budapest, Üllői út 78/B, 1082
Open access

Absztrakt:

A nagy áteresztőképességű molekuláris vizsgálómódszereknek az elmúlt évek során végbement rohamos fejlődése lehetővé tette a tumorok genetikai, epigenetikai, transzkriptom- és fehérjeszintű molekuláris hátterének átfogó és mélyreható elemzését. A nagyszámú tumormintán elvégzett vizsgálatok óriási mennyiségű adatot szolgáltattak, melyek klinikai szempontból történő feldolgozása, értelmezése jelenleg még zajlik, de már most is jelentős új felismerésekhez járult hozzá. Az ilyen típusú kutatások a közelmúltban a prosztatarák esetében is azonosították azokat a legfontosabb molekuláris eltéréseket, melyek szerepet játszanak e tumor kialakulásában és progressziójában. Összefoglaló munkánkban áttekintést nyújtunk a primer és az előrehaladott prosztatarák közelmúltban kidolgozott molekuláris alcsoportbeosztásáról, valamint a leggyakrabban sérült jelátviteli utakról, úgymint az androgénreceptor-, PI3K-, sejtciklust szabályozó útvonalakról és a DNS-hiba-javító mechanizmusokról. Ennek kapcsán áttekintjük a prosztatarák genetikai eltéréseire tervezett célzott terápiás szerek már alkalmazott, valamint még klinikai kipróbálás alatt álló típusait. Orv Hetil. 2019; 160(7): 252–263.

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  • 1

    Kásler M, Ottó Sz, Kenessey I. The current situation of cancer morbidity and mortality in the light of the National Cancer Registry, Hungary. [A rákmorbiditás és -mortalitás jelenlegi helyzete a Nemzeti Rákregiszter tükrében.] Orv Hetil. 2017; 158: 84–89. [Hungarian]

  • 2

    Paulo P, Barros-Silva JD, Ribeiro FR, et al. FLI1 is a novel ETS transcription factor involved in gene fusions in prostate cancer. Genes Chromosomes Cancer 2012; 51: 240–249.

  • 3

    Acs B, Szarvas T, Szekely N, et al. Current state of ERG as biomarker in prostatic adenocarcinoma. Curr Cancer Drug Targets 2015; 15: 643–651.

  • 4

    Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 2015; 163: 1011–1025.

  • 5

    Barbieri CE, Bangma CH, Bjartell A, et al. The mutational landscape of prostate cancer. Eur Urol. 2013; 64: 567–576.

  • 6

    Barbieri CE, Baca SC, Lawrence MS, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012; 44: 685–689.

  • 7

    Blattner M, Lee DJ, O’Reilly C, et al. SPOP mutations in prostate cancer across demographically diverse patient cohorts. Neoplasia 2014; 16: 14–20.

  • 8

    Garcia-Flores M, Casanova-Salas I, Rubio-Briones J, et al. Clinico-pathological significance of the molecular alterations of the SPOP gene in prostate cancer. Eur J Cancer 2014; 50: 2994–3002.

  • 9

    Robinson D, Van Allen EM, Wu Y-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015; 161: 1215–1228.

  • 10

    Wu YM, Cieślik M, Lonigro RJ, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell 2018; 173: 1770–1782.e14.

  • 11

    Grasso CS, Wu YM, Robinson DR, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012; 487: 239–243.

  • 12

    Küronya Zs, Bíró K, Gyergyai F, et al. Androgen receptor-mediated processes in castrate-resistant metastatic prostate cancer. [Androgénreceptor mediálta folyamatok metasztatikus kasztrációrezisztens prosztatadaganatban.] Orv Hetil. 2017; 158: 42–49. [Hungarian]

  • 13

    de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011; 364: 1995–2005.

  • 14

    Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012; 367: 1187–1197.

  • 15

    Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013; 368: 138–148.

  • 16

    Loriot Y, Miller K, Sternberg CN, et al. Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial. Lancet Oncol. 2015; 16: 509–521.

  • 17

    Ferraldeschi R, Nava Rodrigues D, Riisnaes R, et al. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur Urol. 2015; 67: 795–802.

  • 18

    Sun X, Huang J, Homma T, et al. Genetic alterations in the PI3K pathway in prostate cancer. Anticancer Res. 2009; 29: 1739–1743.

  • 19

    Templeton AJ, Dutoit V, Cathomas R, et al. Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08). Eur Urol. 2013; 64: 150–158.

  • 20

    Courtney KD, Manola JB, Elfiky AA, et al. A phase I study of everolimus and docetaxel in patients with castration-resistant prostate cancer. Clin Genitourin Cancer 2015; 13: 113–123.

  • 21

    Toren P, Kim S, Cordonnier T, et al. Combination AZD5363 with enzalutamide significantly delays enzalutamide-resistant prostate cancer in preclinical models. Eur Urol. 2015; 67: 986–990.

  • 22

    Wallin JJ, Edgar KA, Guan J, et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther. 2011; 10: 2426–2436.

  • 23

    de Bono JS, De Giorgi U, Massard C, et al. Randomized phase II study of AKT blockade with ipatasertib (GDC-0068) and abiraterone (Abi) vs. Abi alone in patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel chemotherapy (A. MARTIN Study). J Clin Oncol. 2016; 34(15 Suppl): 5017.

  • 24

    Spratt DE, Zumsteg ZS, Feng FY, et al. Translational and clinical implications of the genetic landscape of prostate cancer. Nat Rev Clin Oncol. 2016; 13: 597–610.

  • 25

    de Leeuw R, Berman-Booty LD, Schiewer MJ, et al. Novel actions of next-generation taxanes benefit advanced stages of prostate cancer. Clin Cancer Res. 2015; 21: 795–807.

  • 26

    Boutros PC, Fraser M, Harding NJ, et al. Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat Genet. 2015; 47: 736–745.

  • 27

    Massie CE, Mills IG, Lynch AG. The importance of DNA methylation in prostate cancer development. J Steroid Biochem Mol Biol. 2017; 166: 1–15.

  • 28

    Daniunaite K, Jarmalaite S, Kalinauskaite N, et al. Prognostic value of RASSF1 promoter methylation in prostate cancer. J Urol. 2014; 192: 1849–1855.

  • 29

    Zhang W, Shu P, Wang S, et al. ZNF154 is a promising diagnosis biomarker and predicts biochemical recurrence in prostate cancer. Gene 2018; 675: 136–143.

  • 30

    Zhang W, Jiao H, Zhang X, et al. Correlation between the expression of DNMT1, and GSTP1 and APC, and the methylation status of GSTP1 and APC in association with their clinical significance in prostate cancer. Mol Med Rep. 2015; 12: 141–146.

  • 31

    Nagy B, Szendrői A, Romics I. Overexpression of CD24, c-myc and phospholipase 2A in prostate cancer tissue samples obtained by needle biopsy. Pathol Oncol Res. 2009; 15: 279–283.

  • 32

    Bharali DJ, Sudha T, Cui H, et al. Anti-CD24 nano-targeted delivery of docetaxel for the treatment of prostate cancer. Nanomedicine 2017; 13: 263–273.

  • 33

    Jimeno A, Gordon M, Chugh R, et al. A first-in-human phase I study of the anticancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors. Clin Cancer Res. 2017; 23: 7490–7497.

  • 34

    Mateo J, Boysen G, Barbieri CE, et al. DNA repair in prostate cancer: biology and clinical implications. Eur Urol. 2017; 71: 417–425.

  • 35

    Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016; 375: 443–453.

  • 36

    Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015; 373: 1697–1708.

  • 37

    Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018; 19: 975–986.

  • 38

    Roscilli G, Gavory G, Lamartina S, et al. PARP inhibitor MK-4827 is synthetic lethal for tumors with homologous recombination defects associated with ATM-deficiency, PTEN-deletion and microsatellite instability (MSI). Cancer Res. 2010; 70(8 Suppl): 685.

  • 39

    Sandhu SK, Schelman WR, Wilding G, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013; 14: 882–892.

  • 40

    Hussain M, Carducci MA, Slovin S, et al. Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer. Invest New Drugs 2014; 32: 904–912.

  • 41

    Hussain M, Daignault-Newton S, Twardowski PW, et al. Targeting androgen receptor and DNA repair in metastatic castration-resistant prostate cancer: results from NCI 9012. J Clin Oncol. 2018; 36: 991–999.

  • 42

    Cheng HH, Pritchard CC, Boyd T, et al. Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer. Eur Urol. 2016; 69: 992–995.

  • 43

    Pomerantz MM, Spisak S, Jia L, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer 2017; 123: 3532–3539.

  • 44

    Nava Rodrigues D, Rescigno P, Liu D, et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest. 2018; 128: 4441–4453.

  • 45

    Beer TM, Kwon ED, Drake CG, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol. 2017; 35: 40–47.

  • 46

    Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184–043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014; 15: 700–712.

  • 47

    Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol. 2018; 29: 1807–1813.

  • 48

    Chila R, Guffanti F, Damia G. Role and therapeutical potential of CDK12 in human cancers. Cancer Treat Rev. 2016; 50: 83–88.

  • 49

    Bajrami I, Frankum JR, Konde A, et al. Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity. Cancer Res. 2014; 74: 287–297.

  • 50

    Kari V, Mansour WY, Raul SK, et al. Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness. EMBO Rep. 2016; 17: 1609–1623.

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