prostaatkanker

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