Prediktív biomarker-jelöltek elemzése az onkológiai betegségek kezelésének javítására

A kutatócsoport vezetői: SZAKÁCS GERGELY és GYŐRFFY BALÁZS

Prediktív biomarker-jelöltek elemzése az onkológiai betegségek kezelésének javítására

Kutatási koncepció:

Az onkológiai betegségek molekulárisan célzott terápiáját azt teszi lehetővé, hogy egyes onkogének aktiválódása miatt a sejtosztódást serkentő jelátviteli útvonalak indulnak be. Mivel ezen jelátviteli aktiválódás a tumor létrejöttének egy korai szakaszában történik meg, ezért valamennyi tumoros sejt hordozza az adott elváltozást. A jelátviteli útvonalak gátlása lehetővé teszi, hogy a tumor növekedés gátlásában jelentős hatást érjünk el, azonban mind a mai napig a célzott terápiában bevezetett szerek esetében nem lehetett kb. 50% feletti válaszadási arányt elérni. Ennek oka, hogy az egyes betegekben más jelátviteli útvonalak aktiválódnak, és eddig nem rendelkezünk olyan biomarkerekket, amelyek ezeket pontosa azonosítani tudják. Kutatásaink során célunk, hogy az emlőtumor célzott terápiájában alkalmazott szerekkel szembeni új biomarkereket azonosítsunk. Ehhez először egy meglevő beteganyagot használunk fel, hogy megfelelő bioinformatikai elemzéssel prediktív markereket azonosítsunk. Ezzel párhuzamosan olyan in vitro modell rendszert fejlesztünk ki, ahol a szóba jövő jelölteket össze tudjuk egymással hasonlítani. Vizsgálataink egyrészt segíteni fognak abban, hogy az onkológiai betegek jobb ellátást kapjanak, másrészt a jeltáviteli útvonalak átkapcsolásainak pontosabb feltérképezést és új farmakológiai gyógyszercélpontok azonosítását is lehetővé fogják tenni.

Kutatási szolgáltatások:

Bioinformatikai analízis

  • Gén-chipek feldolgozása
  • RNA-seq adatok feldolgozása
  • Citotoxicitási esszé (HTS)
  • Esszé fejlesztés
  • Transzporter interakció vizsgálata
  • Trastuzumab-rezisztencia modellek

Emberi erőforrások:

  • Szakács Gergely, MTA TTK EI, csoportvezető
  • Győrffy Balázs, MTA TTK EI, csoportvezető
  • Kurkó Ibolya, asszisztens, MTA TTK EI
  • Kucsma Nóra, tudományos munkatárs, MTA TTK EI
  • Nagy Tibor, MTA TTK EI, tudományos munkatárs, MTA TTK EI
  • Nagy Ádám, MTA TTK EI, tudományos segédmunkatárs, MTA TTK EI

A kutatócsoport friss publikációi:

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  • Bottai G, Raschioni C, Székely B, Di Tommaso L, Szász AM, Losurdo A, Győrffy B, Ács B, Torrisi R, Karachaliou N, Tőkés T, Caruso M, Kulka J, Roncalli M, Santoro A, Mantovani A, Rosell R, Reis-Filho JS, Santarpia L. AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients. NPJ Breast Cancer. 2016 Nov 2;2:16033. doi: 10.1038/npjbcancer.2016.33. eCollection 2016. PubMed PMID: 28721387; PubMed Central PMCID: PMC5515347.
  • Santarpia L, Bottai G, Kelly CM, Győrffy B, Székely B, Pusztai L. Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer. Oncologist. 2016 Sep;21(9):1063-78. doi: 10.1634/theoncologist.2015-0369. Review. PubMed PMID: 27384237.
  • Sadik H, Korangath P, Nguyen NK, Győrffy B, Kumar R, Hedayati M, Teo WW, Park S, Panday H, Munoz TG, Menyhart O, Shah N, Pandita RK, Chang JC, DeWeese T, Chang HY, Pandita TK, Sukumar S. HOXC10 Expression Supports the Development of Chemotherapy Resistance by Fine Tuning DNA Repair in Breast Cancer Cells. Cancer Res. 2016 Aug 1;76(15):4443-56. doi: 10.1158/0008-5472.CAN-16-0774. PubMed PMID: 27302171.
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  • Kulka J, Székely B, Lukács LV, Kiss O, Tőkés AM, Vincze E, Turányi E, Fillinger J, Hanzély Z, Arató G, Szendrői M, Győrffy B, Szász AM. Comparison of Predictive Immunohistochemical Marker Expression of Primary Breast Cancer and Paired Distant Metastasis using Surgical Material: A Practice-Based Study. J Histochem Cytochem. 2016 Apr;64(4):256-67. doi: 10.1369/0022155416639013.
  • Adams BD, Wali VB, Cheng CJ, Inukai S, Booth CJ, Agarwal S, Rimm DL, Győrffy B, Santarpia L, Pusztai L, Saltzman WM, Slack FJ. miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer. Cancer Res. 2016 Feb 15;76(4):927-39. doi: 10.1158/0008-5472.CAN-15-2321.
  • Catalano S, Campana A, Giordano C, Győrffy B, Tarallo R, Rinaldi A, Bruno G, Ferraro A, Romeo F, Lanzino M, Naro F, Bonofiglio D, Andò S, Barone I. Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy. Clin Cancer Res. 2016 May 1;22(9):2271-82. doi: 10.1158/1078-0432.CCR-15-1900.
  • Madaras L, Bálint N, Győrffy B, Tőkés AM, Barshack I, Yosepovich A, Friedman E, Paluch-Shimon S, Zippel D, Baghy K, Timár J, Kovalszky I, Kulka J, Szász AM. BRCA Mutation-Related and Claudin-Low Breast Cancer: Blood Relatives or Stepsisters. Pathobiology. 2016;83(1):1-12. doi: 10.1159/000439135.
  • Giordano C, Chemi F, Panza S, Barone I, Bonofiglio D, Lanzino M, Cordella A, Campana A, Hashim A, Rizza P, Leggio A, Győrffy B, Simões BM, Clarke RB, Weisz A, Catalano S, Andò S. Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity. Oncotarget. 2016 Jan 12;7(2):1262-75. doi: 10.18632/oncotarget.6014.
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  • *Pongor L, Kormos M, Hatzis C, Pusztai L, Szabó A, Győrffy B. A genome-wide approach to link genotype to clinical outcome by utilizing next generation sequencing and gene chip data of 6,697 breast cancer patients. Genome Med. 2015 Oct 16;7(1):104. doi: 10.1186/s13073-015-0228-1. PubMed PMID: 26474971.
  • *Menyhárt O, Santarpia L, Győrffy B. A Comprehensive Outline of Trastuzumab Resistance Biomarkers in HER2 Overexpressing Breast Cancer. Curr Cancer Drug Targets. 2015;15(8):665-83. PubMed PMID: 26452383.
  • *Ligeti B, Pénzváltó Z, Vera R, Pongor S, Győrffy B. A network-based Target Overlap Score for characterizing Drug Combinations: High Correlation with Cancer Clinical Trial Results, PLoS One. 2015 Jun 5;10(6):e0129267. doi: 10.1371/journal.pone.0129267. eCollection 2015. PMID: 26047322.
  • Nguyen VT, Barozzi I, Faronato M, Lombardo Y, Steel JH, Patel N, Darbre P, Castellano L, Győrffy B, Woodley L, Meira A, Patten DK, Vircillo V, Periyasamy M, Ali S, Frige G, Minucci S, Coombes RC, Magnani L. Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion. Nat Commun. 2015 Nov 27;6:10044. doi: 10.1038/ncomms10044.
  • Budczies J, Bockmayr M, Denkert C, Klauschen F, Lennerz JK, Győrffy B, Dietel M, Loibl S, Weichert W, Stenzinger A. Classical pathology and mutational load of breast cancer – integration of two worlds. Journal of Pathology: Clinical Research. 2015;1(4):225-238.
  • Broude EV, Győrffy B, Chumanevich AA, Chen M, McDermott MS, Shtutman M, Catroppo JF, Roninson IB. Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer. Curr Cancer Drug Targets. 2015;15(8):739-49. PubMed PMID: 26452386.
  • Periyasamy M, Patel H, Lai CF, Nguyen VT, Nevedomskaya E, Harrod A, Russell R, Remenyi J, Ochocka AM, Thomas RS, Fuller-Pace F, Győrffy B, Caldas C, Navaratnam N, Carroll JS, Zwart W, Coombes RC, Magnani L, Buluwela L, Ali S. APOBEC3B-Mediated Cytidine Deamination Is Required for Estrogen Receptor Action in Breast Cancer. Cell Rep. 2015 Oct 6;13(1):108-21. doi: 10.1016/j.celrep.2015.08.066. Epub 2015 Sep 24. PubMed PMID: 26411678.
  • Magnani L, Patten DK, Nguyen VT, Hong SP, Steel JH, Patel N, Lombardo Y, Faronato M, Gomes AR, Woodley L, Page K, Guttery D, Primrose L, Fernandez Garcia D, Shaw J, Viola P, Green A, Nolan C, Ellis IO, Rakha EA, Shousha S, Lam EW, Győrffy B, Lupien M, Coombes RC. The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer. Oncotarget. 2015 Sep 8;6(26):21878-91. PubMed PMID: 26215677.
  • Jin K, Park S, Teo WW, Korangath P, Cho SS, Yoshida T, Győrffy B, Goswami CP, Nakshatri H, Cruz LA, Zhou W, Ji H, Su Y, Ekram M, Wu Z, Zhu T, Polyak K, Sukumar S. HOXB7 Is an ERα Cofactor in the Activation of HER2 and Multiple ER Target Genes Leading to Endocrine Resistance. Cancer Discov. 2015 Sep;5(9):944-59. doi: 10.1158/2159-8290.CD-15-0090. Epub 2015 Jul 15. PubMed PMID: 26180042;
  • Lan L, Holland JD, Qi J, Grosskopf S, Vogel R, Győrffy B, Wulf-Goldenberg A, Birchmeier W. Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice. EMBO J. 2015 Jun 3;34(11):1493-508. PMID: 25736378.
  • Grabner B, Schramek D, Mueller KM, Moll HP, Svinka J, Hoffmann T, Bauer E, Blaas L, Hruschka N, Zboray K, Stiedl P, Nivarthi H, Bogner E, Gruber W, Mohr T,  Zwick RH, Kenner L, Poli V, Aberger F, Stoiber D, Egger G, Esterbauer H, Zuber J, Moriggl R, Eferl R, Győrffy B, Penninger JM, Popper H, Casanova E. Disruption of  STAT3 signalling promotes KRAS-induced lung tumorigenesis. Nat Commun. 2015 Mar 3;6:6285. PubMed PMID: 25734337.
  • Budczies J, Pfitzner BM, Győrffy B, Winzer KJ, Radke C, Dietel M, Fiehn O, Denkert C. Glutamate enrichment as new diagnostic opportunity in breast cancer. Int J Cancer. 2015 Apr;136(7):1619-28. PMID: 25155347.
  • Labidi-Galy SI, Clauss A, Ng V, Duraisamy S, Elias KM, Piao HY, Bilal E, Davidowitz RA, Lu Y, Badalian-Very G, Győrffy B, Kang UB, Ficarro S, Ganesan S, Mills GB, Marto JA, Drapkin R. Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors. Oncogene. 2015 Jan 15;34(3):373-83. PMID: 24469047.
  • Sänger N, Ruckhäberle E, Győrffy B, Engels K, Heinrich T, Fehm T, Graf A, Holtrich U, Becker S, Karn T. Acid ceramidase is associated with an improved prognosis in both DCIS and invasive breast cancer. Mol Oncol. 2015 Jan;9(1):58-67. PMID: 25131496.
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  • Nguyen NT, Vendrell JA, Poulard C, Győrffy B, Goddard-Léon S, Biècheg I, Corbo L, Le Romancer M, Bachelot T, Treilleux I, Cohen PA. A functional interplay between ZNF217 and Estrogen Receptor alpha exists in luminal breast cancers, Mol Oncol  2014 Dec;8(8):1441-57.
  • Teleki I, Szász AM, Maros ME, Győrffy B, Kulka J, Meggyeshazi N, Kiszner G, Balla P, Samu A, Krenács T. Correlations of differentially expressed gap junction connexins Cx26, Cx30, Cx32, Cx43 and Cx46 with breast cancer progression and prognosis. PLoS One. 2014 Nov 10;9(11):e112541. doi: 10.1371/journal.pone.0112541.
  • Shi W, Balazs B, Qi Y, Györffy B, Wang B, Liu CG,  Shiang CY, Valero V, Moulder-Thompson S, Avritscher R, Powis G, Hortobagyi GN, Natowicz R, Weinstein J, Symmans WF, Pusztai L. Combined analysis of gene expression, DNA copy number and mutation profiling data to display biological process anomalies in individual cancers. Breast Cancer Res Treat, 2014 Apr;144(3):561-8.
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  • *Pénzváltó Zs, Tegze B, Szász AM, Sztupinszki Zs, Likó I, Szendrői A, Schäfer R, Győrffy B. Identifying Resistance Mechanisms against five Tyrosine Kinase Inhibitors Targeting the ERBB/RAS Pathway in 45 Cancer Cell Lines. PLoS One, 2013;8(3):e59503. doi: 10.1371/journal.pone.0059503.
  • *Mihály Zs, Győrffy B. Improving Pathological Assessment of Breast Cancer by Employing Array-Based Transcriptome Analysis, Microarrays 2013, 2(3), 228-242; doi: 10.3390/microarrays2030228
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  • Holland JD, Győrffy B, Vogel R, Eckert K, Valenti G, Fang L, Lohneis P, Elezkurtaj S, Ziebold U, Birchmeier W. Combined Wnt/β-Catenin, Met, and CXCL12/CXCR4 Signals Characterize Basal Breast Cancer and Predict Disease Outcome. Cell Rep. 2013 Dec 12;5(5):1214-27. doi: 10.1016/j.celrep.2013.11.001
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  • Malek A, Győrffy B, Catapano CV, Schäfer R. Selection of optimal combinations of target genes for therapeutic multi-gene silencing based on miRNA co-regulation. Cancer Gene Therapy, 2013 May;20(5):326-9. doi: 10.1038/cgt.2013.20
  • Maciejczyk A, Szelachowska J, Czapiga B, Matkowski R, Halon A, Györffy B, Surowiak P. Elevated BUBR1 Expression Is Associated with Poor Survival in Early Breast Cancer Patients--16 Years Follow-up Analysis. J Histochem Cytochem. 2013 May;61(5):330-9. doi: 10.1369/0022155413480148.
  • Szász AM, Eklund AC, Li Q, Sztupinszki Z, Tőkés AM, Rowan A, Székely B, Kiss A, Szendrői M, Győrffy B, Szállási Z, Swanton C, Kulka J. The CIN4 chromosomal instability qPCR classifier defines tumour aneuploidy and stratifies outcome in grade 2 breast cancer. PLoS One, 2013;8(2):e56707. doi: 10.1371/journal.pone.0056707.
  • Maciejczyk A, Lacko  A, Ekiert  M, Jagoda E, Wysocka  T, Matkowski  R , Halon  A, Győrffy  B, Lage  H, Surowiak P. Elevated nuclear S100P expression is associated with poor survival in early breast cancer patients. Histology and Histopathology, 2013 Apr;28(4):513-24.

Laboratóriumok, helyiségek:

  • Steril sejttenyésztő labor

Műszerpark:

  • Hamilton STAR Let folyadék adagoló robot rendszer
  • EnSpire mikro lemez olvasó (Perkin Elmer)