Download Castration Resistant Prostate Cancer

Androgen Receptor signaling axis
in castration-resistant prostate cancer
Lucarelli Giuseppe, MD, PhD
Urology and Kidney Transplantation Unit
Dept of Emergency and Organ Transplantation
University of Bari
This program is supported by an educational donation provided by
Castration Resistant Prostate Cancer
Prostate cancer disease continuum
Death
Docetaxel/chemotherapy
Castration
Tumour
volume
2nd-line
hormonal
therapies
Bicalutamide
Flutamide
Nilutamide
Abiraterone
Cabazitaxel
Local
therapy*
Continued AR
signalling
Symptoms
Asymptomatic
Non-metastatic
Metastatic
Hormone-sensitive
Castration-resistant
Time
Kohli & Tindall. Mayo Clin Proc 2010;85:77–86.
AR, androgen receptor
CASTRATE RESISTANT PROSTATE CANCER
PATHOPHYSIOLOGY
Testosterone
serum levels
(ng/dl)
Disease
progression
tumor
burden
(PSA levels)
150
100
50
Castration
threshold
Serum testosterone
20
0
time
Stimulation of Tumor Growth
De Bono ESMO Educational Program, Genitourinary Cancers 2010 modified
The road to resistance
Pathway
AR dependence
Mechanism
Hypersensitive
AR dependent
AR amplification
AR splice variants
Promiscuous
AR dependent
AR mutation
Outlaw
AR dependent
Cross-talk with GF
signaling pathways
Bypass
AR indipendent
Parallel survival
pathways
Lurker cells
AR indipendent
Epithelial stem cells
AR amplification
AR gene amplifications are observed in 20-25% of CRPC
but they are very rare in primary tumors
Chen CD et al, Nature Medicine 10, 33 - 39 (2004)
Higher AR levels convert antagonists to agonists
Chen CD et al, Nature Medicine 10, 33 - 39 (2004)
AR splice variants
Expression of
Cell-cycle genes (UBE2C)
Upregulation of
steroidogenic enzymes
AR mutations
T877A mutant
(Thr→Ala)
E2/Prog
L701H mutant
(Leu→His)
Double T877A
L701H mutant
(Zhao XY, Nat Med: 6, 2000)
E2/Prog
H874Y mutant
(His→Tyr)
Inappropriate
interaction with
AR coactivators
DHT 100 nM
DHT 100 nM
Q640Stop mutation generates
a constitutively activated mutant AR
AR Coactivators
Coactivators
PCa Expression
ARA70
Controversial data
ARA54
Up-regulated
ARA55
p300
SRC1
Up-regulated
TIF2
PIAS
RAC3
Up-regulated
Up-regulated
Up-regulated
Function
Enhances AR activities
or Tumor suppressor?
Enhances AR activation
(Estradiol+Flutamide)
″
Ligand indipendent
activation by IL-6
Enhances AR activation
(Adrenal androgens)
″
Correlation with
grade & stage
AR coactivators augment functional activity of the receptor
by interacting with histones and are implicated
in ligand indipendent activation of the AR
Outlaw receptor
RAS
ADT results in de-repression of alternative
survival pathways and in recalibration of prostate
cancer tissue androgen levels leading to partial
restoration of AR transcriptional activity.
Karantos et al. Oncogene 2013 (in press)
MDV-3100-Enzalutamide
Enzalutamide is an AR signalling inhibitor that inhibits AR signalling in
three distinct ways:
2. Impairs nuclear translocation
1. Blocks AR binding
Cytoplasm
DHT
Enzalutamide
AR
3. Blocks DNA binding
and activation
Nucleus
Enzalutamide
2–3 fold lower affinity than DHT
Tran et al. Science 2009;324:787–90; Watson et al. Proc Natl Acad Sci USA 2010;107:16759–65.
Enzalutamide
Androgen metabolism in prostate cancer
Intratumoral androgens in CRPC tumors are maintained at
levels sufficient to activate the AR signaling pathway
Activated steroidogenesis pathways provide an adaptive
response to ADT, facilitating CRPC tumor survival in a low
exogenous androgen environment.
The maintenance of intratumoral androgens can be accounted
for in part by intratumoral or intracrine biosynthesis of steroid
hormones, either via the uptake and conversion of adrenal
androgens or potentially via de novo steroidogenesis.
Classic pathway
Backdoor pathway
Expression of steroidogenic enzyme transcripts in
primary and metastatic prostate tumors
Soft tissue metastases from CRPC
shows
elevated
testosterone
compared to primary tumors
Transcripts encoding all enzymes
involved
in
the
sequential
biosynthesis of testosterone and DHT
from cholesterol precursors were
expressed in the majority of
castration-resistant metastatic tumors
examined
Montgomery RB, Cancer Res 2008;11, 68
Meccanismo d’azione di abiraterone
Steroidogenesi
ipokaliemia
Ipertensione
sovraccarico di fluidi
Cholesterol
Desmolase
Renin-angiotensin
Pregnenolone
Pregnenolo
Progesterone
Deoxycorticosterone
Corticosterone
Aldosterone
CYP17
X
17αhydroxylase
17α –OHprogesterone
17α-OHpregnenolone
11-Deoxycortisol
Cortisol
ACTH
X
CYP17
C17,20-lyase
5α-reductase
DHEA
Androstenedione
Testosterone
DHT
CYP19:
aromatasi
Abiraterone
Estradiolo
Yang, Drugs. 2011; Attard, JCO 2008
Meccanismo d’azione di abiraterone
Steroidogenesi
Cholesterol
Basse dosi di steroidi minimizzano la tossicità
mineralcoticoide - correlata
Desmolase
Renin-angiotensin
Pregnenolone
Progesterone
Deoxycorticosterone
Corticosterone
Aldosterone
CYP17
X
17αhydroxylase
17α –OHprogesterone
17α-OHpregnenolone
11-Deoxycortisol
Cortisol
ACTH
X
CYP17
C17,20-lyase
5α-reductase
DHEA
Androstenedione
Testosterone
DHT
CYP19:
aromatasi
Abiraterone + prednisone
Estradiolo
Yang, Drugs. 2011; Attard, JCO 2008
Stromal-epithelial interactions and intratumoral androgen biosynthesis
Alterations in androgen transport
normal
BPH
SLCO1B3
PCa
Wright JL, Cancer Epidemiol Biomarkers Prev. 2011
Conclusions
Persistent activation of AR signaling in CRPC suggests that
a majority of prostate cancers progress through pathways that
continue to activate the cellular AR program.
While the introduction of potent steroidogenic inhibitors such as
abiraterone, in combination with novel AR inhibitors such as
MDV3100, holds significant promise for the concept of multitargeted AR pathway blockade, the optimal timing, sequence, and
potential combinatorial strategies using new AR pathway inhibitors
are critical unanswered questions in the treatment of men with
CRPC.
Prostate cancer is not the only cause of death in men