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Fig4

A novel combination therapy for pancreatic cancer.

Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma

Nature Medicine, 2015

Major finding: Dual inhibition of BET proteins and HDACs synergistically suppresses PDAC development and maintenance.

Mechanism: JQ1 inhibits MYC and inflammatory cytokines, and synergizes with SAHA to activate p57 and induce death.

Impact: PDAC is sensitive to epigenetic-based therapies, which may be quickly implemented for patient use.

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Screen Shot 2015-09-29 at 13.15.26ss

A novel regulatory mechanism can be manipulated to treat pancreatic cancer.

SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer

Nature, 2014

Major finding: SMYD3-mediated MAP3K2 methylation activates RAS signaling and drives carcinogenesis in vivo.

Mechanism: Methylation of MAP3K2 by SMYD3 disrupts binding to PP2A and activates MEK1/2 signaling.

Impact: Those results reveal an unexpected role for lysine methylation in a kinase signalling pathway and establish SMYD3 as a potential therapeutic target.

 

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Scaffold blockade inhibits pancreatic cancer.

IQGAP1 Scaffold-Kinase Interaction Blockade Selectively Targets RAS-MAP Kinase Driven Tumors

Nature Medicine, 2013

Major finding: Disruption of IQGAP1 scaffold function inhibits oncogenic ERK signaling without toxicity.

Mechanism: An IQGAP1 peptide reduces RAS/RAF–driven tumor growth and bypasses vemurafenib resistance.

Impact: Blockade of scaffold-kinase interactions can complement direct kinase inhibition for pancreatic cancer treatment.

 

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gandd

SMYD2 is a critical regulator of tumorigenesis in the pancreas and lung.

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer.

Genes and Development, 2016

Major finding: Loss of SMYD2 function reduces the growth of various tumor cell populations while its overexpression is pro-tumorigenic.

Mechanism: SMYD2 methylation of MK3 stress kinase promotes the proliferation and the survival of pancreas and lung cancer cells.

Impact: Inhibition of SMYD2 cooperates with standard chemotherapy to treat pancreatic cancer cells and reduces growth of patient derived tumors. 

 

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Selected publications:

  1. Jahchan NS, Lim JS, Bola B, Morris K, Seitz G, Tran KQ, Xu L, Trapani F, Morrow CJ, Cristea S, Coles GL, Yang D, Vaka D, Kareta MS, George J, Mazur PK, Nguyen T, Anderson WC, Dylla SJ, Blackhall F, Peifer M, Dive C, Sage J. Identification and Targeting of Long-Term Tumor-Propagating Cells in Small Cell Lung Cancer. Cell Reports. 2016

  2. Krampitz GW, George BM, Willingham SB, Volkmer JP, Weiskopf K, Jahchan N,Newman AM, Sahoo D, Zemek AJ, Yanovsky RL, Nguyen JK, Schnorr PJ, Mazur PK, Sage J, Longacre TA, Visser BC, Poultsides GA, Norton JA, Weissman IL. Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors. Proc Natl Acad Sci U S A. 2016
  3. ••• Reynoird N*, Mazur PK*, Stellfeld T, Flores NM, Lofgren SM, Carlson SM,Brambilla E, Hainaut P, Kaznowska EB, Arrowsmith CH, Khatri P, Stresemann C,Gozani O, Sage J. Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer. Genes Dev. 2016 *equally contributed
  4. ••• Mazur PK*#, Herner A*, Mello SS, Wirth M, Hausmann S, Sánchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noël PB, Braren R, Erkan M, Kleeff J, Sipos B, Sayles LC, Heikenwalder M, Heßmann E, Ellenrieder V, Esposito I, Jacks T, Bradner JE, Khatri P, Sweet-Cordero EA, Attardi LD, Schmid RM, Schneider G, Sage J#, Siveke J# Nature Medicine. 2015. *contributed significantly #co-coresponding authors.
  5. ••• Mazur PK*, Reynoird N*, Khatri P, Jansen PW, Wilkinson AW, Liu S, Barbash O, Van Aller GS, Huddleston M, Dhanak D, Tummino PJ, Kruger RG, Garcia BA, Butte AJ, Vermeulen M, Sage J, Gozani O. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature. 2014. *equally contributed
  6. ••• Jameson KL*, Mazur PK*, Zehnder AM, Zhang J, Zarnegar B, Sage J, Khavari PA, IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAPK-driven tumors. Nature Medicine. 2013 *equally contributed
  7. ••• Baumgart A*, Mazur PK*, Anton M, Rudelius M, Schwamborn K, Feuchtinger A, Behnke K, Walch A, Braren R, Peschel C, Duyster J, Siveke JT, Dechow T. Opposing role of Notch1 and Notch2 in a Kras(G12D)-driven murine non-small cell lung cancer model. Oncogene. 2014 Feb *equally contributed
  8. Chen R, Khatri P*, Mazur PK*, Polin M, Zheng Y, Vaka D, Hoang CD, Shrager J, Xu Y, Vicent S, Butte AJ, Sweet-Cordero EA. A meta-analysis of lung cancer gene expression identifies PTK7 as a survival gene in lung adenocarcinoma. Cancer Research. 2014 *equally contributed
  9. Jahchan NS, Dudley JT*, Mazur PK*, Flores N, Yang D, Palmerton A, Zmoos AF, Vaka D, Tran KQ, Zhou M, Krasinska K, Riess JW, Neal JW, Khatri P, Park KS, Butte AJ, Sage J. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discovery. 2013 *equally contributed
  10. Ardito CM, Grüner BM, Takeuchi KK, Lubeseder C, Mazur PK, Delgiorno KE, Carpenter ES, Halbrook CJ, Hall JC, Pal D, Briel T, Herner A, Trajkovic-Arsic M, Sipos B, Liou GY, Storz P, Murray NR, Threadgill DW, Sibilia M, Washington MK, Wilson CL, Schmid RM, Raines EW, Crawford HC, Siveke JT. EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis. Cancer Cell. 2012.
  11. Grüner BM, Hahne H, Mazur PK, Trajkovic-Arsic M, Maier S, Esposito I, Kalideris E, Michalski CW, Kleeff J, Rauser S, Schmid RM, Küster B, Walch A, Siveke JT. MALDI imaging mass spectrometry for in situ proteomic analysis of preneoplastic lesions in pancreatic cancer. PLoS One. 2012
  12. Aichler M, Seiler C, Tost M, Siveke J, Mazur PK, Da Silva-Buttkus P, Bartsch DK, Langer P, Chiblak S, Dürr A, Höfler H, Klöppel G, Müller-Decker K, Brielmeier M, Esposito I. Origin of pancreatic ductal adenocarcinoma from atypical flat lesions: a comparative study in transgenic mice and human tissues. J Pathol. 2012
  13. ••• Mazur PK, Riener MO, Jochum W, Kristiansen G, Weber A, Schmid RM, Siveke JT. Expression and Clinicopathological Significance of Notch Signaling and Cell-Fate Genes in Biliary Tract Cancer. Gastroenterology. 2011.
  14. Viatour P, Ehmer U, Saddic LA, Dorrell C, Andersen JB, Lin C, Zmoos AF, Mazur PK, Schaffer BE, Ostermeier A, Vogel H, Sylvester KG, Thorgeirsson SS, Grompe M, Sage J. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med. 2011.
  15. Heid I, Lubeseder C, Sipos B, Mazur PK, Lesina M, Schmid RM, Siveke JT. Early requirement of Rac1 in a mouse model of pancreatic cancer. Gastroenterology. 2011
  16. ••• Mazur PK, Einwächter H, Lee M, Sipos B, Nakhai H, Rad R, Zimber-Strobl U, Strobl LJ, Radtke F, Klöppel G, Schmid RM, Siveke JT. Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proc Natl Acad Sci USA. 2010.
  17. ••• Mazur PK, Grüner BM, Nakhai H, Sipos B, Zimber-Strobl U, Strobl LJ, Radtke F, Schmid RM, Siveke JT. Identification of epidermal Pdx1 expression discloses different roles of Notch1 and Notch2 in murine Kras(G12D)-induced skin carcinogenesis in vivo. PLoS One. 2010.
  18. Geisler F, Nagl F, Mazur PK, Lee M, Zimber-Strobl U, Strobl LJ, Radtke F, Schmid RM, Siveke JT. Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology. 2008
  19. Nakhai H, Siveke JT, Klein B, Mazur PK, Algül H, Radtke F, Strobl L, Zimber-Strobl U, Schmid RM. Conditional ablation of Notch signaling in pancreatic development. Development. 2008
  20. Siveke JT, Lubeseder-Martellato C, Lee M, Mazur PK, Nakhai H, Radtke F, Schmid RM. Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology. 2008

Selected reviews

  1. Mazur PK, Sage J. Pancreatic cancer takes its Toll. J Exp Med. 2015
  2. Mazur PK, Neff F, Herner A, Siveke JT. Current Methods in Mouse Models of Pancreatic Cancer, Methods in Molecular Biology volume on Mouse Models of Cancer, Humana Press (book chapter), 2015
  3. Mazur PK, Siveke JT. Genetically engineered mouse models of pancreatic cancer: unravelling tumour biology and progressing translational oncology. Gut. 2012
  4. Jagielski T, van Ingen J, Rastogi N, Dziadek J, Mazur PK, Bielecki J. Current methods in the molecular typing of Mycobacterium tuberculosis and other mycobacteria. Biomed Res Int. 2005

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