8e Nascholing Targeted Therapy Prostaatcarcinoom André Bergman NKI-AvL TARGETED THERAPY: PROSTAAT CARCINOOM 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 TARGETED THERAPY: PROSTAAT CARCINOOM Gen regulatie: het chromatine TARGETED THERAPY: PROSTAAT CARCINOOM Chang and O’Malley, 1976. 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 TARGETED THERAPY: PROSTAAT CARCINOOM HRPC werd CRPC: ng/dL 300 - 1200 HRPC Hormoon Refractair Prostaat Carcinoom 50 20 10 Normale spiegels Castratieniveau HRPC TARGETED THERAPY: PROSTAAT CARCINOOM HRPC werd CRPC: ng/dL 300 - 1200 CRPC Castratie Resistent Prostaat Carcinoom 50 20 10 Normale spiegels Castratieniveau CRPC TARGETED THERAPY: PROSTAAT CARCINOOM Androgen receptor signaling Androgen-responsive cell Testosterone DHT AR HSP CYP17A P P AR AR AR HSP P P AR AR CoF Cytoplasm PSA Growth Survival DNA Nucleus Androgen responsive element (ARE) TARGETED THERAPY: PROSTAAT CARCINOOM Androgen receptor signaling Androgen-responsive cell Abiraterone ✖ Testosterone DHT AR HSP CYP17A P P AR AR AR HSP P P AR AR CoF Cytoplasm PSA Growth Survival DNA Nucleus Androgen responsive element (ARE) TARGETED THERAPY: PROSTAAT CARCINOOM Androgen receptor signaling Androgen-responsive cell Abiraterone ✖ Testosterone DHT AR HSP CYP17A Enzalutamide ✖ P P AR AR AR HSP P P AR AR CoF Cytoplasm PSA Growth Survival DNA Nucleus Androgen responsive element (ARE) TARGETED THERAPY: PROSTAAT CARCINOOM Nieuwe antihormonale middelen post-docetaxel: Abiraterone: CYP17A remming Enzalutamide: ARSI Abiraterone (median, mos): 14.8 Prednisone (median, mos): 10.9 Enzalutamide (median, mos): 18.4 Placebo (median, mos): 13.6 HR (95% CI): 0.79 (0.66-0.95) P-value: 0.0151 HR (95% CI): 0.63 (0.53-0.75) P-value: <0.001 De Bono et al, N Engl J Med 2011; 364: 1995-2005 Scher et al, N Engl J Med 2012; 367: 1187-1197 TARGETED THERAPY: PROSTAAT CARCINOOM Hoe AR signalering nog beter remmen? 1. Combinatie Abiraterone en Enzalutamide TARGETED THERAPY: PROSTAAT CARCINOOM Hoe AR signalering nog beter remmen? 1. Combinatie Abiraterone en Enzalutamide GFR AR HSP PI3 K P PTEN P AR AR AKt P P AR AR mTOR CoF Nucleus Carver et al, Cancer Cell; 2011: 19, 575-586 TARGETED THERAPY: PROSTAAT CARCINOOM Hoe AR signalering nog beter remmen? 1. Combinatie Abiraterone en Enzalutamide GFR AR HSP PI3 K P PTEN P AR AR PHLP P P P AR AR AKt mTOR CoF Nucleus Carver et al, Cancer Cell; 2011: 19, 575-586 TARGETED THERAPY: PROSTAAT CARCINOOM Hoe AR signalering nog beter remmen? 1. Combinatie Abiraterone en Enzalutamide AR HSP P 2. Combinatie Abiraterone/ Enzalutamide met PI3K/Akt remmer GFR HER2/3 PI3 K AR stability AR transcription P AR AR PHLP P P P AR AR PTEN AKt mTOR CoF Nucleus Carver et al, Cancer Cell; 2011: 19, 575-586 TARGETED THERAPY: PROSTAAT CARCINOOM Hoe AR signalering nog beter remmen? 1. Combinatie Abiraterone en Enzalutamide AR HSP P 2. Combinatie Abiraterone/ Enzalutamide met PI3K/Akt remmer GFR HER2/3 PI3 K AR stability AR transcription P AR AR PHLP P P P AR AR PTEN AKt mTOR CoF Nucleus Carver et al, Cancer Cell; 2011: 19, 575-586 TARGETED THERAPY: PROSTAAT CARCINOOM Relatie AR en Docetaxel? Docetaxel remt AR signalering Gan et al, Cancer Res 2009: 69, 8386-8394 Zhu et al, Cancer Res 2010: 70, 7992-8002 Darshan et al, Cancer Res 2011: 71, 6019-6029 Van Soest et al, Eur J Cancer 2013; 49: 3821-3830 Met kruisresistentie tot gevolg TARGETED THERAPY: PROSTAAT CARCINOOM Targeted therapy Docetaxel combinatie studies • Alle afgeronde fase III-studies vinden geen toegevoegde waarde: • NePro: 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 “Docetaxel is a bad bride!” – TRAPEZE: docetaxel ± samarium ± zometa • Lopende fase III-studies: • SYNERGY: docetaxel + OGX-011 (Custirsen) TARGETED THERAPY: PROSTAAT CARCINOOM Cabozantinib: MET en VEGFR2-remmer Indrukwekkende fase II-data (171 patienten): 68% verbeterde skeletscan PFS 23.9 vs 5.9 weken Fase III studie (COMET-1) afgerond Smith et al, JCO 2013; 31: 412-419 TARGETED THERAPY: PROSTAAT CARCINOOM Androgen receptor (AR)binding: AR modifications Exome sequencing AR translocation to the nucleus: Inhibited by drugs Number of DNA binding sites (FAIRE-seq) Biomarkers of response prediction and resistance to antihormonal treatment AR binding to ARE Gene activation Gene activation pattern (Chip-seq) Chip-seq Alternative growth signals Gene expression RNA seq A R Immunoprecipitation Reverse cross-link Sequence DNA TARGETED THERAPY: PROSTAAT CARCINOOM Predicting Response to Enzalutamide as a Second Line Treatment for Metastasized Castration Resistant Prostate Cancer Patients: a biomarker design study (PRESTO-study) TARGETED THERAPY: PROSTAAT CARCINOOM Dank voor uw aandacht
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