8 e Nascholing Targeted Therapy. Prostaatcarcinoom. André Bergman NKI-AvL
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1 8 e Nascholing Targeted Therapy rostaatcarcinoom André Bergman NKI-AvL
2 TGETED THERAY: ROSTAAT CCINOOM Disclosure belangen spreker (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties met bedrijven Sponsoring of onderzoeksgeld Honorarium of andere (financiële) vergoeding Aandeelhouder Andere relatie, namelijk Zie hieronder Bedrijfsnamen Amgen, Astellas Sanofi, Amgen, Jansen, Astellas Geen Geen
3 TGETED THERAY: ROSTAAT CCINOOM Gen regulatie: het chromatine
4 TGETED THERAY: ROSTAAT CCINOOM Chang and O Malley, N Engl J Med. Wang et al., 2009 Cell Taslim et al., 2012 Nucleic acids res Sun et al., 2009 Mol Endo Shemshedini et al., 1991 EMBO J Amir et al., 2003 JBC
5 TGETED THERAY: ROSTAAT CCINOOM HRC werd CRC: ng/dl Normale spiegels HRC Hormoon Refractair rostaat Carcinoom Castratieniveau HRC
6 TGETED THERAY: ROSTAAT CCINOOM HRC werd CRC: ng/dl Normale spiegels CRC Castratie Resistent rostaat Carcinoom Castratieniveau CRC
7 TGETED THERAY: ROSTAAT CCINOOM Androgen receptor signaling Testosterone Androgen-responsive cell CY17A DHT HS HS Cytoplasm CoF SA Growth Survival Nucleus DNA Androgen responsive element (E)
8 TGETED THERAY: ROSTAAT CCINOOM Androgen receptor signaling Androgen-responsive cell Abiraterone Testosterone CY17A DHT HS HS Cytoplasm CoF SA Growth Survival Nucleus DNA Androgen responsive element (E)
9 TGETED THERAY: ROSTAAT CCINOOM Androgen receptor signaling Androgen-responsive cell Abiraterone Testosterone CY17A DHT HS Enzalutamide HS Cytoplasm CoF SA Growth Survival Nucleus DNA Androgen responsive element (E)
10 TGETED THERAY: ROSTAAT CCINOOM Nieuwe antihormonale middelen post-docetaxel: Abiraterone: CY17A remming Enzalutamide: SI Abiraterone (median, mos): 14.8 rednisone (median, mos): 10.9 HR (95% CI): 0.79 ( ) -value: Enzalutamide (median, mos): 18.4 lacebo (median, mos): 13.6 HR (95% CI): 0.63 ( ) -value: <0.001 De Bono et al, N Engl J Med 2011; 364: Scher et al, N Engl J Med 2012; 367:
11 TGETED THERAY: ROSTAAT CCINOOM Hoe signalering nog beter remmen? 1. Combinatie Abiraterone en Enzalutamide
12 TGETED THERAY: ROSTAAT CCINOOM Hoe signalering nog beter remmen? 1. Combinatie Abiraterone en Enzalutamide HS GFR I3 K TEN AKt CoF mtor Nucleus Carver et al, Cancer Cell; 2011: 19,
13 TGETED THERAY: ROSTAAT CCINOOM Hoe signalering nog beter remmen? 1. Combinatie Abiraterone en Enzalutamide HS GFR I3 K TEN HL AKt CoF mtor Nucleus Carver et al, Cancer Cell; 2011: 19,
14 TGETED THERAY: ROSTAAT CCINOOM Hoe signalering nog beter remmen? 1. Combinatie Abiraterone en Enzalutamide 2. Combinatie Abiraterone/ Enzalutamide met I3K/Akt remmer HS HER2/3 CoF I3 stability K transcription HL GFR Nucleus AKt TEN mtor Carver et al, Cancer Cell; 2011: 19,
15 TGETED THERAY: ROSTAAT CCINOOM Hoe signalering nog beter remmen? 1. Combinatie Abiraterone en Enzalutamide 2. Combinatie Abiraterone/ Enzalutamide met I3K/Akt remmer HS HER2/3 CoF I3 stability K transcription HL GFR Nucleus AKt TEN mtor Carver et al, Cancer Cell; 2011: 19,
16 TGETED THERAY: ROSTAAT CCINOOM Relatie en Docetaxel? Docetaxel remt signalering Gan et al, Cancer Res 2009: 69, Zhu et al, Cancer Res 2010: 70, Darshan et al, Cancer Res 2011: 71, Met kruisresistentie tot gevolg Van Soest et al, Eur J Cancer 2013; 49:
17 TGETED THERAY: ROSTAAT CCINOOM Docetaxel combinatie studies Alle afgeronde fase III-studies vinden geen toegevoegde waarde: Nero: docetaxel ± oraal bifosfonaat (risedronate) MAINSAIL: docetaxel ± lenolidamide ASCENT-II: doceaxel ± calcitriol VITAL-II: docetaxel ± GVAX vaccin SWOG S0421: docetaxel ± atrasentan Enthuse: docetaxel ± zibotentan CALLGB90401: docetaxel ± bevacizumab Venice: docetaxel ± aflibercept Ready: docetaxel ± dasatinib TRAEZE: docetaxel ± samarium ± zometa Lopende fase III-studies: SYNERGY: docetaxel + OGX-011 (Custirsen) Targeted therapy Docetaxel is a bad bride!
18 TGETED THERAY: ROSTAAT CCINOOM Cabozantinib: MET en VEGFR2-remmer Indrukwekkende fase II-data (171 patienten): 68% verbeterde skeletscan FS 23.9 vs 5.9 weken Fase III studie (COMET-1) afgerond Smith et al, JCO 2013; 31:
19 TGETED THERAY: ROSTAAT CCINOOM Androgen receptor ()binding: modifications Exome sequencing translocation to the nucleus: Inhibited by drugs Number of DNA binding sites (FAIRE-seq) binding to E Gene activation Gene activation pattern (Chip-seq) Biomarkers of response prediction and resistance to antihormonal treatment Chip-seq Alternative growth signals Gene expression RNA seq A R Reverse cross-link Immunoprecipitation Sequence DNA
20 TGETED THERAY: ROSTAAT CCINOOM redicting Response to Enzalutamide as a Second Line Treatment for Metastasized Castration Resistant rostate Cancer atients: a biomarker design study (RESTO-study)
21 TGETED THERAY: ROSTAAT CCINOOM Dank voor uw aandacht
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