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ONCOGENIC TRANSCRIPTION FACTORS 30 10 2015 Viral oncogenes – 1970s Oncogene v-myb v-myc v-fos v-jun v-ets Disease Gene myeloblastosis (avian) c-myb myelocytomatosis (avian) c-myc fbj osteosarcoma (murine) c-fos 'ju-nana' sarcoma (avian) c-jun erythroblastosis [E26] (avian) ets1/erg Human disease T-cell leukemia Burkitt's lymphoma Breast Ca. Breast Ca. PCa/AML/Sarcoma Retroviral-mediated transduction Hijack Host DNA MECHANISMS OF ONCOGENIC TRANSFORMATION GENETIC DEFECT • GENE AMPLIFICATION • CHROMOSOMAL REARRANGEMENT GENE OVEREXPRESSION GENE FUSION • MUTATION • OVEREXPRESSION MECHANISMS OF ONCOGENIC TRANSFORMATION FUNCTIONAL EFFECT • HYPER-ACTIVATION • HYPER-REPRESSION • ACTIVATOR REPRESSOR • SHIFT DNA BINDING SITE • DOMINANT NEGATIVE • ALTERED SUBCELLULAR LOCALIZATION ON Differentiation Stemness Cell. 2006 Nov 3;127(3):469-80. Colon carcinoma β-catenin mutation APC mutation Cell. 2006 Nov 3;127(3):469-80. - Differentiation - Proliferation - Survival Nature Reviews Immunology 8, 380-390 (May 2008) T-cell acute linfoblastic leukemia HD domain mutation Nonsense mutation Nature Reviews Immunology 8, 380-390 (May 2008) Myc:Max:Mad network Myc over-expressed in 50% human tumors Adapted from : Amati, B., S. R. Frank, et al. (2001). "Function of the c-Myc oncoprotein in chromatin remodeling and transcription." Biochim Biophys Acta 1471(3): M135-45. c-myc target genes cyclin A , p53, Gadd45, Cdc25 The Encyclopedia of Cancer, 2002 c-myc driven oncogenesis ON ON Adapted from: Shachaf CM et al. Nature, 2004, 431(7012):1112-7 c-myc amplification Melanoma normal tumor chr. 8 myc 8 14 IgH/myc translocation Burkitt’s Lymphoma TMPRSS2/ERG Prostate carcinoma TMPRSS2 1 2 3 ERG 14 1 2 3 4 11 TMPRSS2/ERG 1 2 3 4 11 • differentiation • migration • invasion • metastasis AML1–CBFb complex AML1 AML1 = RUNX1 AML1/ETO Acute myeloid leukemia Chr.21 Chr.8 AML1 ETO AML1/ETO most common chromosomal translocation in acute myeloid leukemia (AML) AML1/ETO AML1 TAD DBD AML1/ETO RD DBD AML1/ETO www.science.ngfn.de RARa CoR CoR RA RARa PML/RARa Acute promyelocytic leukemia CoR CoR RA RA RARaRA RA RA PML PLZF/RARa Acute promyelocytic leukemia CoR CoR RA RA RARaRA RA RA PLZF CoR CoR TARGETING • block expression Antisense RNAi • block activity Peptides Small-molecules ANTISENSE AAAAA PML/RARa Acute promyelocytic leukemia CoR CoR RARa PML PML/RARa - Antisense PML/RARa Control Gambacorti-Passerini C, Mologni L, et al., Blood, 1996 PML/RARa Adapted from: Mologni L, et al., Cancer Res, 2001 ANTISENSE PRO CON • Specific • Degradation (PO) • Versatile • Immune response (PS) • Simple design • Cell penetration (PNA) • Cheap RNA INTERFERENCE (RNAi) small interfering RNA short-hairpin RNA siRNA shRNA Colon carcinoma β-catenin mutation APC mutation Cell. 2006 Nov 3;127(3):469-80. b-Catenin RNAi Van de Wetering et al., EMBO Rep., 2003 b-Catenin RNAi Colon carcinoma 0 1 2 3 4 5 b-Catenin actin -DOX 100,000 50,000 +DOX 0 1 2 3 4 Mologni et al., Cancer Res., 2010 RNAi PRO CON • Potent • Delivery • Specific • Degradation • Versatile • Inflammatory response • Simple design PEPTIDES PEPTIDES Peptide BPI Diffuse large B cell lymphoma N-CoR BCL-6 Differentiation Peptide BPI N-CoR TAT--Gly-Arg-Ser-Ile-His-Glu-Pro-Arg CD80 6 4 BCL-6 2 Polo JM et al., Nat. Med., 2004 PEPTIDES PRO CON • Specific • Unstable • Versatile • Degradation • Simple design • Immune response • Cell penetration Peptidomimetic RI-BPI TAT—D-Arg-Pro-Glu-His-Ile-Ser-Arg-Gly degradation Cerchietti et al., Blood, 2009 STAPLED PEPTIDES Advantages Stability Helicity Affinity Cell penetration Notch1 stapled peptide T-LLA Moellering et al., Nature, 2009 Notch1 stapled peptide control non-staple -secretase inhibitor staple Moellering et al., Nature, 2009 SMALL-MOLECULE INHIBITORS Le Pourcelet, et al., Cancer Cell, 2004 b-catenin activity PKF115-584 PKF115-584 Le Pourcelet, et al., Cancer Cell, 2004 MUTANT B-CAT NORMAL B-CAT Le Pourcelet, et al., Cancer Cell, 2004 SMALL-MOLECULE INHIBITORS PRO CON • Cell penetration • Specificity/Tox • No immune response • PK • Drug-like • Difficult to design
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