Nieuwe Ontwikkelingen in de Behandeling van Kanker
prostaatkanker
Testosteron
Testosteron geeft zakenvrouwen ’boost’ AMSTERDAM - Wil je als zakenvrouw slagen in de financiële wereld dan heb je geluk als je over een hoog testosterongehalte beschikt.
1. LHRH agonist
(zoladex, lucrin, eligard)
2. Anti-androgenen
Abiteraterone MDV3100
Cholesterol Cyp11A
Pregnenolone
Cyp17
Cyp17
17α-hydroxypregnenolone
Progesterone
Cyp17
Cyp17
17α-hydroxyprogesterone
DHEA
Cyp17/HSD3β2
Androstenedione
CYP17: een belangrijk enzyme
17βHSD
Testosterone CYP3A4/3A5
SRD5A2 SRD5A1
CYP1B1
Testosterone breakdown
DHT AR
AAG
Abiteraterone (na chemotherapie) 16/34 (47%) pts ≥50% PSA daling 22/34 (65%) pts ≥30% PSA daling
MDV3100: Androgeen Receptor Antagonist (small molecule)
Hormonale therapie • voor start chemotherapie • na chemotherapie
nieuwe studies
Nieuwe Ontwikkelingen in de Behandeling van Kanker
chemotherapie
Wanneer te starten met chemotherapie ? Botuitzaaingen: • • • •
pijn destructie dwarslesie beenmerg suppressie
Uitzaaingen in lymfklieren: • obstructie Æ nierfunctie verlies
Secondary Objectives Response Rates Docetaxel 3 wkly Pain Response Rate* n, evaluable Response rate (%) P-value (vs. mitoxantrone) PSA Response Rate* n, evaluable PSA response rate (%) P-value (vs. mitoxantrone) Tumor Response Rate* n, evaluable Response rate (%) P-value (vs. mitoxantrone)
Docetaxel wkly
Mitoxantrone
153 35 0.01
154 31 0.07
157 22 ‒
291 45 0.0005
282 48 <0.0001
300 32 ‒
141 12 0.1
134 8 0.5
137 7 ‒
* Determined only for patients with pain or PSA ≥20 or measurable disease at baseline, respectively
Anti-angiogenesis Remming bloedvatvorming
Docetaxel + Thalidomide Overleving
P=0.0407
Thalidomide + Docetaxel median 26.9 months
Docetaxel Median 14 months
Dahut et al J Clin Oncol, 2004
Remming bloedvatvorming
Bevacizumab CALBG Phase II study: N=97
estramustine docetaxel bevacizumab
day 1-5 day 2 day 2
PSA response
81%
Median survival
21 months
Anti -angiogenesis
Docataxel + Thalidomide + Bevacizumab
II (N=60)
90% PSA
63% Response
Docetaxel + sunitinib (Sutent) II (N=44)
50% PSA
39% Response
Chemotherapie • start niet te laat • combinatie met remmers van bloedvatvorming hoopvol
nieuwe studies
Verspreiding van tumorcellen
HGF/SF
Ras
c-Met
Gab1
Proliferation
Sos
Grb2
Raf
Shp2
ERK/MAPK
100 % van de uitzaaingen hebben c-MET (receptor)
Control
Scatter factor
Verspreiding van tumorcellen
Bloedvatvorming Studie: Mitoxantrone + AMG102
Immunotherapie (versterking afweer tegen kanker)
T-lymfocyte
Dendritische cel
Provenge (dendritische cel therapie)
Recombinant Prostatic Acid Phosphatase (PAP) antigen combines with resting antigen presenting cell (APC)
APC takes up the antigen
Antigen is processed and presented on surface of the APC
Fully activated, the APC is now sipuleucelT INFUSE PATIENT
Active Tcell
T-cells proliferate and attack cancer cells
The precise mechanism of sipuleucel-T in prostate cancer has not been established.
Sipuleucel-T activates T-cells in the body
Inactive T-cell
Sipuleucel-T (Provenge®) Manufacturing Process Day 1
Day 2-3
Day 3-4
Leukapheresis
Sipuleucel-T is manufactured
Patient is infused
Apheresis Center
Dendreon
Doctor’s Office
COMPLETE COURSE OF THERAPY: 3 CYCLES
D9901 Fig 2. Primary end point, time to disease progression (intent-totreat population)
Small, E. J. et al. J Clin Oncol; 24:3089-3094 2006
Cop yrigh t © A m erican Socie ty o f Clinical O ncolog y
D9901 Fig 3. Final overall survival (intent-to-treat population)
Small, E. J. et al. J Clin Oncol; 24:3089-3094 2006
Cop yrigh t © A m erican Socie ty o f Clinical O ncolog y
Ipilimumab (MDX-010)
• anti-human CTLA-4 Antibody
• blocks the binding of CTLA-4 to B7
• fully human IgG1k antibody
• does not mediate ADCC
Ipilimumab (MDX-010)
Radiotherapy of bone lesions + Ipilimumab Radiotherapy bone lesions + Ipilimumab
Prostate cancer (immunotherapy)
Irradiated, autologous tumor cells transduced with the GM-CSF gene
Dendritic cell
T - cell Anti-tumor Activity
® GVAX
Phase 2 Studies in HRPC
• Pijn ter plaatse van injecties • Jeuk, zwelling • Overleving: bemoedigend 2.5 jaar
Prostate GVAX® Phase 3 Program GVAX
VITAL-1 HRPC w/ mets Chemo-naive asymptomatic
Docetaxel + Pred N = 600
Docetaxel + GVAX VITAL-2 Docetaxel + Pred
HRPC w/ mets Taxane-naive symptomatic N = 600
s u r v i v a l s u r v i v a l
GVAX Immunotherapy (CG1940/CG8711) + Ipilimumab (MDX-010: anti-CTLA-4) for HRPC
Prostate Cancer Program VUmc 1. rising PSA
ET-1A
urologie
2. HRPC before chemo G-VAX + MDX Abiraterone
retreatment pending
3. HRPC 1e line
NEPRO
open
5. HRPC 2nd line
AMG102
open
5. HRPC 2nd line
RT + MDX
pending
6. HRPC 3rd lne
MDV3100
pending
