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Epigenetic Regulation of Hematological Malignancies

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Epigenetic Regulation of Hematological Malignancies EPIGENETIC REGULATION OF HEMATOLOGICAL MALIGNANCIES Elke De Bruyne, PhD Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel No conflicts of intrest to disclose 14-2-2013 Pag. 1 EPIGENOMICS . Both genetic and epigenetic alterations play a fundamental role in tumor pathogenesis Epigenetic changes = all heritable modifications of the genome which are not caused by changes in the primary DNA sequence and that result in phenotypic changes Pag. EPIGENOMICS Post-translational histone modifications DNA methylation Pag. Arrowsmith C et al, Nature Reviews Drug Discovery, 2012, vol 11. HISTONE POST-TRANSLATIONAL MODIFICATIONS De Bruyne E et al, Springer Science, 2013. Pag. ALTERNATIVE TRANSCRIPTIONAL OUTCOMES . DNA methylation and histone deacetylation: repressive . Histone acetylation: active . Histone methylation: both depending on site and degree of methylation - H3K27me3, H3K9 me2/3, H4K20me3 are repressive marks - H3K4me2/3, H3K36me2/3 and H3K79me are active marks Co-operate intensively to organize the chromatin structure and control gene expression Pag. CHROMATINE MODIFYING PROTEINS Acetylases (HATs) Deacetylases (HDACs) Bromodomain Methylases (DNMTs, HMTs) Demethylases (HDMs) Chromodomain Kinases Phosphatases PHD finger WD40 repeat Pag. Gardner K et al, Journal of Molecular biology, 2011, Vol 409. EPIGENETIC LANDSCAPE IS DISTURBED IN CANCER CELLS: Global hypomethylation: Genomic instability Site specific hypermethylation: Loss-of-function of genes Pag. McCabe M et al, Clinical Cancer Research 2009, Vol 15. RECURRENT EPIGENETIC SILENCED GENES . Cell cycle progression (e.g., Rb, p14, p15, p16, p57, p73, …) . Survival (e.g., caspase-8, DAPK1, BIM, TMS-1, …) . Growth factor signaling (e.g., SOCS1, SOCS3, CRBP1, RAR- beta2,…) . DNA damage/ repair (e.g., Fancomi anemia-BRCA pathway members, GSTπ, hMLH1, MGMT …) . Metastatic potential (e.g., TIMP3, E-cadherin, CD9, …) . Angiogenesis (e.g., VHL, BNIP3, BNIP3L, IGFBP3, EGLN2, …) ………… adverse prognosis Pag. CAUSE OF GLOBAL SHIFTS IN CHROMATINE MODIFICATION, STRUCTURE AND FUNCTION? . Mutations of chromatin modifying proteins Malignancy writers erasers readers AML Dnmt3a, EZH2, MLL, UTX, TET ASXL1, PHF6 NSD family, CBP, p300, Jak2 MDS Dnmt3a, EZH2, MLL, UTX, TET ASXL1 Jak2 CML EZH2, Jak2 UTX, TET ASXL1 ALL Dnmt3a, EZH2, MLL, UTX, TET ASXL, PHF6 CBP, Jak2 MM MMSET UTX Lymphoma Dnmt3a, EZH2, MLL, TET CBP, p300, Jak2 Pag. EPIGENETIC REPROGRAMMING . Epigenetic modifications are reversible . Plethora of epigenetic-modulating agents have been designed to target the epigenetic modifiying proteins . Most advanced in terms of clinical applications: - DNA methyltransfersases inhibitors (DNMTi) - Histone deacetylase inhibitors (HDACi) mostly in the field of hematological malignancies Pag. HYPOMETHYLATING CYTOSINE ANALOGUES . Azacytidine (Vidaza) and Decitabine (Dacogen) . Dual mode of action: - low dose: hypomethylation (DNMTi) - high dose: cytotoxicity (DNA damage, cell cyle arrest and apoptosis) . FDA approved in high-risk MDS (standard of care) RD up to 18 months Fenaux P et al, Lancet Oncology, 2009, Vol 10. Pag. HYPOMETHYLATING CYTOSINE ANALOGUES . Promising activity in elderly AML patients: trend for improved overall survival . Remaining hematological malignancies: only modest single agent activity . Main side-effects: myelosuppression, injection site side-effects, nausea, vomiting, diarrhea Pag. HDACi Class Compound Study phase Hydroxamic acid TSA Voronistat (SAHA) FDA approved Panobinostat (LBH589) III Belinostat (PXD101) II LAQ824 I IFT2357 II Short-chain fatty Sodium butyrate acids Valproic acid I AN-9 I II Benzamidines Entinostat (MS275) II Mocetinostat II (MGCD0103) Cyclic peptides Romidepsin (FK228) FDA approved Aplicidin Pag. HDACi . Potent preclinical anti-tumor activity and remarkable tumor specificity . Mechanisms of action are pleiotropic: - cell cycle arrest - apoptosis - immuno modulation - angiostatic . Clinical efficacy for CTCL, PTCL, HL, AML . MM, CLL, CML, ALL, MDS: response unpredictable and rather poor . Main side-effects: fatigue, diarrhea, nausea, anemia and thrombocytopenia Pag. EPIGENETIC MODULATING DRUGS . Single agent activity is only modest . Therapy is not curative and resistance develops . Ascribed to: 1. Response depends on the compound, concentration and time of exposure and cellular context → most relevant target(s) responsible for the anti-cancer activity remain undefined 2. No validated biomarkers available to identify patients whom would benefit from epigenetic targeted treatment or predict for clinical response Pag. NEW AVENUES FOR (PRE)CLINICAL RESEARCH . Test new dosing schedules and compare routes of administration (SGI-110) . Design (new) drug combinations: with conventional and/or other epigenetic agents . Unravel underlying mechanisms, especially in vivo . Develop new agents with higher specificity (e.g. HTMi, HDMi, specific HDACi, ….) . Identify patients who would benefit from epigenetic targeted treatment (= personalized treatment) Pag. MULTIPLE MYELOMA (MM)= MODEL FOR EPIGENETIC DYSREGULATION – Different 5TMM models moderate growth (12w) 5T2 osteolytic lesions rapid growth (3-4w) 5T33 no osteolytic lesions In vitro cell line (5T33vt) – Similar characteristics as human disease Pag. JNJ-26481585 (JNJ-85) IN 5TMM MODEL (Johnson&Johnson) . Novel, second generation hydroxamate based pan- HDACi, with significantly improved pharmacodynamic parameters. Potent anti-tumor activity in preclinical solid and hematological tumor models. Currently in phase II clinical trial (CTCL). Pag. EFFECT ON HISTONE ACETYLATION AND PROLIFERATION Histone acetylation Proliferation Deleu S et al, Leukemia, 2009, Vol 23. Pag. EFFECT ON CELL CYCLE * * * 5T33MMvt STR-10 HDACi in MM 14/02/2013 | pag. 20 Pag. EFFECT ON APOPTOSIS Pag. JNJ-85 IN THE 5TMM MODEL – PROPHYLATIC AND THERAPEUTIC SETTING 5T33MM Week 4 Day 0 •Vehicle •JNJ-85 (20mg/kg, Tumorload every other day,s.c.) Bone disease 5T2MM Day 0 Week 8 Week 12 M-protein Pag. IN VIVO ANTI-MM ACTIVITY (I) BM plasmacytosis Serum M-protein 5T33MM 80 * * 4 60 * * 3 40 2 20 1 Paraprotein (g/dl) Paraprotein 0 0 % MM cells in the bonecells %MM marrow Naive Vehicle 20mg/kg Naive Vehicle 20mg/kg *P<0.0001 *P<0.0001 JNJ-26481585 JNJ-26481585 5T2MM 2,5 80 2 60 * * * * 1,5 40 1 20 Paraprotein (g/dl)Paraprotein % MM cells in the BM the in cells MM % 0,5 0 0 Naive Vehicle 20mg/kg Naive Vehicle 20mg/kg *p<0,001 JNJ-26481585 *p<0,001 JNJ-26481585 Pag. IN VIVO ANTI-MM ACTIVITY (II) Pag. JNJ-85 IN COMBINATION WITH BORTEZOMIB (Bz) Week 0 Week 8 Week 12 M-protein i.v. injection of Sacrifice 5T2MM cells Treatment of the mice (s.c.) • Vehicle • Bortezomib (0.8mg/kg, twice weekly) • Bortezomib (0.6mg/kg, twice weekly) • JNJ-85 (1.25mg/kg, every other day,s.c.) • Combo (low) Deleu S et al, Cancer Reserach, 2009, Vol 69. Pag. IN VIVO ANTI-MM ACTIVITY (I) Sarah Deleu, Fig.1 A BMTumor plasmacytosisload in BM B Serum MParaprotein-protein 60 2,5 * * * 50 * * * 2,0 * * * 40 (g/dl) in the BM the in 1,5 30 cells 1,0 20 Paraprotein %MM %MM 10 0,5 0 Bz Bz + 5T2MM + 5T2MM Bz Bz Bz 0,0 Bz 5T2MM + + 5T2MM 5T2MM + + 5T2MM JNJ JNJ Naive Naive Vehicle Vehicle 5T2MM + + 5T2MM JNJ + 5T2MM + + 5T2MM + 5T2MM + JNJ + 5T2MM + + 5T2MM 5T2MM + + 5T2MM + 5T2MM (0.6mg/kg) (0.6mg/kg) (0.6mg/kg) (0.8mg/kg) (0.6mg/kg) (0.8mg/kg) (0.6mg/kg) - - 85 85 - - 85 85 C Microvessel density (MVD) * 30 * * * * 25 staining 20 Pag. CD31 bloodvessels by 15 of Nr 10 counted 5 Bz Bz 5T2MM + + 5T2MM 0 Naive Bz 5T2MM + + 5T2MM JNJ Vehicle + JNJ + 5T2MM + + 5T2MM + 5T2MM + 5T2MM (0.6mg/kg) (0.6mg/kg) (0.8mg/kg) (0.6mg/kg) - 85 - 85 Sarah Deleu, Fig.2 5T2MM + Bz + JNJ- A B 85 Bone Volume * 6 5T2MM + * JNJ-85 5 * * 1. 2. 3. 5T2MM + * 4 Bz Trabecular * CD31 CD31 staining (0.6mg/kg) Volume 3 5T2MM + Volume/ Volume/ Bz 2 (0.8mg/kg) Bone Bone 4. 5. 6. % 1 5T2MM + Vehicle 0 Bz Bz Bz 5T2MM + 5T2MM 5T2MM + + 5T2MM Naive Vehicle + JNJ + JNJ + 5T2MM 5T2MM + + 5T2MM + 5T2MM (0.6mg/kg) (0.6mg/kg) (0.8mg/kg) (0.6mg/kg) Naive - 85 - Sarah Deleu, Fig.2 85 Trabecular C Trabecular number Volume/ Bone % A B Bone Volume 1,2 * * * * 5T2MM + * Bz + JNJ-85 nr 0,8 * 1. 2. 3. Trabecular 5T2MM + MM MM ACTIVITY (III) JNJ-85 - Trabecular 0,4 Volume/ 5T2MM + Bz (0.6mg/kg)Bone number % 4. 5. 6. 0 5T2MM + Bz Bz Bz Bz Bz Bz 5T2MM + 5T2MM 5T2MM + 5T2MM 5T2MM + + 5T2MM 5T2MM + + 5T2MM Naive Naive Vehicle Vehicle Bz (0.8mg/kg) JNJ + JNJ + 5T2MM JNJ JNJ + 5T2MM + + 5T2MM 5T2MM + + 5T2MM + 5T2MM 5T2MM + + 5T2MM + 5T2MM (0.6mg/kg) (0.6mg/kg) (0.6mg/kg) (0.6mg/kg) (0.8mg/kg) (0.6mg/kg) (0.8mg/kg) (0.6mg/kg) - - 85 85 - - 85 85 5T2MM + + JNJ85 1.25 C Trabecular number Vehicle Trabecular Pag. Naive IN VIVO IN VIVO ANTI nr Trabecular nr Trabecular Bz Bz Bz 5T2MM + 5T2MM 5T2MM + + 5T2MM Naive Vehicle JNJ JNJ + 5T2MM + + 5T2MM 5T2MM + + 5T2MM + 5T2MM (0.6mg/kg) (0.6mg/kg) (0.8mg/kg) (0.6mg/kg) - 85 - +85 JNJ85 1.25 CD31 CD31 staining Osteoblasts Nr Sarah Deleu, Fig.3 Sarah Deleu, Fig.3 Sarah Deleu, Fig.3 A Nr osteoclasts per mm B Nr osteoblasts per mm A Nr osteoclasts per mm B Nr osteoblasts per mm A Nr osteoclasts per mm B Nr osteoblasts per mm 5 * * * 30 * * * 4 * * /mm * * 25 /mm /mm /mm MM MM ACTIVITY (III) /mm * /mm 3 - 20 osteoclasts osteoclasts 15 osteoclasts osteoblasts 2 Nr osteoblasts Nr osteoblasts Nr 10 Nr Nr Nr 1 5 Bz Bz + 5T2MM Osteoclasts Bz Bz + 5T2MM 0 Bz Bz Bz Bz + 5T2MM 5T2MM + 5T2MM + 5T2MM 5T2MM + 5T2MM + 5T2MM Bz 0 JNJ Naive Naive 5T2MM + 5T2MM + 5T2MM JNJ Bz Bz + 5T2MM Naive Naive Bz Bz + 5T2MM Vehicle Vehicle Bz JNJ Naive Naive Vehicle Vehicle Bz 5T2MM + + 5T2MM + 5T2MM JNJ + Bz + 5T2MM 5T2MM + + 5T2MM Bz Vehicle Vehicle 5T2MM + + 5T2MM + 5T2MM JNJ + Bz 5T2MM + + 5T2MM JNJ (0.6mg/kg) (0.6mg/kg) + + JNJ 5T2MM + 5T2MM + 5T2MM + 5T2MM JNJ (0.8mg/kg) (0.6mg/kg) (0.6mg/kg) (0.6mg/kg) JNJ 5T2MM + + 5T2MM + 5T2MM JNJ + (0.8mg/kg) (0.6mg/kg) 5T2MM + + 5T2MM (0.6mg/kg) (0.6mg/kg) (0.8mg/kg) (0.6mg/kg) 5T2MM + + 5T2MM + 5T2MM JNJ + 5T2MM + + 5T2MM (0.6mg/kg) (0.6mg/kg) + + JNJ 5T2MM + 5T2MM + 5T2MM (0.8mg/kg) (0.6mg/kg) 5T2MM + 5T2MM - (0.6mg/kg) (0.6mg/kg) (0.8mg/kg) (0.6mg/kg) (0.6mg/kg) (0.6mg/kg) (0.8mg/kg) (0.6mg/kg) - 85 - - 85 85 Nr 85 - - 85 85 - 85 - - - 85 85 85 - - 85 85 Pag.
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