current landscapes in the management of prostate cancer
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Christoper Logothetis, M.D., Dept. Chair, Dept. of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center: Current Landscapes in the Management of Prostate Cancer Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CMETRANSCRIPT
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Christopher J. Logothetis, M.D.
Serial Microenvironment Targeted Therapy Of Prostate Cancer
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• Chemotherapy• The role of bone • Accelerating progress• Summary advances
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Docetaxel in Castrate Resistant & Metastatic Prostate Cancer
Tannock et al
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Control Primary
Systemic Therapy
Optimize therapy in advanced setting: Expect increased benefit when applied
in earlier disease state.
Solid Tumor Therapy Paradigm
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Accepted Model of Cancer Progression
Treatment Sensitive Treatment Resistant
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Accepted Model of Cancer Progression
Treatment Sensitive Treatment Resistant0 20 40 60 80 100 120
0
0.2
0.4
0.6
0.8
1.0
# At Risk, "AA": 135 92 55 27 12# At Risk, "CH": 125 92 58 32 7
Median (95% CI)
Androgen Ablation 65 (56, 93) Chemohormonal 74 (61, 120+)
P = 0.41
Months from Initiation of Hormone Therapy
Ove
rall
Surv
ival P
robabili
ty
A
No effect on survival(androgen dependent PCa)
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Solid Tumor Therapy Paradigm
Therapeutic agents effective in far advanced disease
states will be more effective in earlier states
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Autocrine
Paracrine
PhysiologyEpithelial dysregulation
Time
Leth
ality
Che
mot
hera
py re
sist
ance
Proposed Progression Model
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• Chemotherapy• The role of bone • Accelerating progress• Summary advances
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Epithelial
Bone development program
Bone -Epithelial Central to Prostate Cancer Progression
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0
.2
.4
.6
.8
1
Ove
rall
Sur
viva
l
0 10 20 30 40 50 60 70 80
Time from Registration, mo
Adriamycin OnlySr-89/AdriamycinNon-Randomized
Bone Consolidation Trial
Tu et al Lancet 2003
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MDA-BF-1 in Activated Osteoblasts in Bone Metastasis
Vakar-Lopez et al. J. Pathol. 2004, 203: 688-695
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PC/MDA-BF1
6 weeks
control Side
control Side
PC3
MDA-BF-1 inhibits osteolytic response of PC-3 cells in vivo
6 weeks
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Epithelium
Stroma
Localized Lymph Node Bone
Androgen independent
MDA- BF1 in ProgressiveProstate Cancer
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PCa cells bone
osteoblast
old lamella bone
new woven bone
MDA-BF-1
MDA-BF-1
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“Two Compartment Model”
Interaction of Autocrine & Paracrine loops in Epithelial and Host drives the organ
specific progression of prostate cancer
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Epithelial
Bone microenvironment
Microenvironment in Prostate Cancer
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Prostate Cancer Progression Model
Bone Microenvironment Dependence
Nora Navone et al
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Normal Physiologic
State
Early Cancer
Invasive Cancer
Early-Stage Metastatic
Cancer
Lethal Cancer
Endocrine-to-Paracrine Androgen Signaling Transition
Efstathiou et al. Clin Cancer Res. 2010.
Role of endocrine-to-paracrine androgen signaling transition
Proposed Model of Prostate Cancer Progression
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Androgen-Mediated Progression of Prostate Cancer
Endocrine
Gonadal
Adrenal
Testosterone
AR DHT
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Androgen-Mediated Progression of Prostate Cancer
Endocrine
Gonadal
Adrenal
Testosterone
AR DHT
Microenvironment
CYP17
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Where Androgen Signaling & Tumor Microenvironment TransectEndocrine
Gonadal
Adrenal
Testosterone
AR DHT
Microenvironment
CYP17
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Androgen rich
AR Genomic Signaling
PSA
AR AR
AR
CYP17
AR
Increased intracrine steroid biosynthesis
PSA
mAR mAR
mAR
AR overexpressionmutant/isoform AR
SRC/SH2
ARP
P
Cell survival/anti-apoptotic
Interface of AR signalingwith other pathways (src, cMET, Hh and others)
Adaptive Response of Androgen Signaling in CRPC
Castration/ Disease Progression
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Androgen rich
AR Genomic Signaling
PSA
AR AR
AR
CYP17
AR
Increased Intracrine steroid biosynthesis
Adaptive Response of Androgen Signaling in CRPC
Castration/ Disease Progression
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COU-AA-301: Abiraterone Acetate Improves Overall Survival in Metastatic CRPC
De Bono et al. N Engl J Med. In press.
21
HR = 0.646 (0.54-0.77) P < 0.0001
Placebo: 10.9 months (95% CI: 10.2-12.0)
Abiraterone acetate: 14.8 months (95% CI: 14.1-15.4)
100
80
60
40
20
Surv
ival
(%)
00 3 6 9 12 15 18
PlaceboAA
Time to Death (Months)
CRPC, castrate resistant prostate cancer.
FDA Approved Apr 28, 2011
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Bone Discovery PlatformStudy Design
Bone Marrow Biopsy and Aspirate Intervals
Baseline* Maximum Response*/**
Progression*Week 8*
*Tissue:1) Serum and plasma blood and bone marrow aspirate2) Transilial bone marrow biopsy
**Variable time point/optional
Abiraterone Acetate
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Maximizing Yield of “Blind” Transilial Bone Marrow Biopsy
CT Directed
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Abiraterone Acetate Bone Marrow Trial 2007-0590
(56 pts)
Bone marrow involvement detected by transilial biopsy (all time points)
30 (54%)
Baseline tumor infiltrated bone marrow 27 (48%)
Paired tumor infiltrated bone marrow (>5%) 17 (30%)
Baseline specimens evaluable for IHC (>5% tumor infiltration)
25 (45%)
Baseline tumor infiltration ≥20% (FISH) 15 (27%)
Bone marrow aspirates 50 (89%)
Cancer Acquisition Rates (“Directed” Transilial Bone Marrow Biopsy)
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≥ 30% Reduction: 59% (34/56)
≥ 50% Reduction: 48% (28/56)
≥ 90% Reduction: 16% (9/56)
Modulation of Serum PSA Following Abiraterone Acetate Treatment
PSA
Cha
nge
(%)
-90
-75
-50
-30
0
25
50
75
100
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Pretreatment Androgen SignalingPretreatmentAndrogen Signaling Components
0No
expression
1(<25%)
2(25%-75%)
3(>75%)
Nuclear AR 0 0 8 17
CYP17 4 5 8 8
MeanRange in ng/mL (n)
Bone marrow aspirate testosterone (ng/mL)
0.0560.0000-0.257 (50)
Bone marrow aspirate dihydrotestosterone
0.001(0.000-0.04)
Blood testosterone (ng/mL)
0.0440.0000-0.214 (52)
Blood dihydrotestosterone
0.01(0.00-0.0459)
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AR CYP17
Persistent Androgen Signaling in CRPC With Bone Metastases
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Pretreatment CYP17 Expression in the Tumor Correlates With Increased BMA
Testosterone Concentration
CYP17 Expression in Tumor ≥10%
No CYP17 Expression in Tumor
P Value,Wilcoxon
BMA-T, ng/mL (mean ± SD) 0.074 ± 0.070 0.026 ± 0.019 0.045
0.0
0.05
0.10
0.15
0.20
0.25
BMA
-T.P
lasm
a M
S (n
g/m
L)
CYP17 ≥10% No CYP17 Expression
BMA, bone marrow aspirate; BMA-T, bone marrow aspirate, testosterone.
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Blood Testosterone
0.000.050.100.150.200.25
Week 8
Conc
entr
atio
n (n
g/m
L)
Pretreatment
Bone Marrow Testosterone
0.000.050.100.150.200.250.30
Week 8
Conc
entr
atio
n (n
g/m
L)
End of Study Pretreatment
Sustained Depletion of Testosterone Following Abiraterone Acetate
End of Study
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Intense and Homogeneous Nuclear AR Expression With CYP17 Co-expression
Correlate With Longer Treatment DurationPrimary Resistance*
N (%)Stable Response
N (%)P Value
>90% nuclear AR expression and
≥10% CYP17 expression in the tumor epithelium 1 (7) 13 (93)
<0.001Lack of one or both 10 (91) 1 (9)
*Time to treatment discontinuation
<4 months (122 days) Time (Days)
Prog
ress
ion
Prop
orti
on
0 100 200 300 400 500
0.0
0.2
0.4
0.6
0.8
1.0
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Persistent nuclear AR expression in patients with benefit from ABI at end of treatment
Nuclear AROverexpression at
Progression
Benefit 9/11
PrimaryResistance
2/6
(P value :0.04)
Pretreatment End of Treatment
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Modulation of AR Copy Number(Preliminary Observations)
0 20 40 60 80 100 120 140 160 180
0 wks
Responder , 8 wks
0 wks
Responder , 8 wks
0 wksResponder , 8 wks
0 wksResponder, 8 wks
0 wksPrimary Resistance 8 wks
0 wksPrimary Resistance, 8 wks
Copy NumberqPCR on ≥500 cells.
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Androgen rich
AR Genomic Signaling
PSA
AR AR
AR
CYP17
AR
Increase steroid biosynthesis
PSA
mAR mAR
mAR
AR Overexpression mutant/isoform AR
Adaptive Response of Androgen Signaling in CRPC
Castration/ Disease Progression
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Bone Marrow Biopsy Study
MDV 3100
Baseline Week 8 Progression
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Modulation of Serum PSA Following MDV3100 Treatment
PSA
Cha
nge
(%)
-90-75
-50
-30
0
25
50
75
100 ≥ 30% Reduction: 56% (29/52)
≥ 50% Reduction: 46% (24/52)
≥ 90% Reduction: 20% (10/52)
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Nuclear Localization Cytoplasmic Localization
Shift in AR subcellular localization following MDV3100
in patients with PSA decline
Pretreatment Week 8
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AR Inhibition (MDV 3100) Increased Testosterone Concentration
Pretreatment(mean)
Week 8(mean)
P value(wilcoxon)
Bone Marrow Τ 0.026 0.04 0.0001
Bone Marrow DHT 0.0 0.003 0.335
Blood Τ 0.041 0.066 <0.0001
Blood DHT 0.002 0.007 0.008
Patients
T C
hang
e in
BM
(%)
-100-80
-60
-40
-20
20
4060
80
100
PatientsT
Cha
nge
in P
lasm
a (%
)
-100
-80
-60-40
-20
20
40
60
80
100
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Persistent androgen signaling driven by altered receptor or
adaptive steroid synthesis is a hallmark of prostate cancer progression and a central component of the tumor
microenvironment
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Increased pSrc expression correlates with resistance to MDV3100
Non responders Responders P valueWilcoxon’s rank test
Mean pSrc Expression (%)(Range)
70(0-90)
10(0-30)
0.002
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Androgen rich
AR Genomic Signaling
PSA
AR AR
AR
CYP17
AR
Increase steroid biosynthesis
PSA
mAR mAR
mAR
Generation of mutant/isoform AR
SRC/SH2
ARP
P
Cell survival/anti-apoptotic
Non-genomic AR signalingActivation of SRC kinase,cMET,Hh
Adaptive Response of Androgen Signaling in CRPC
Castration/ Disease Progression
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Increased Phospho-Src at Progression More Evident in Patients With Primary Resistance to Abiraterone
Acetate (Preliminary Observations)
P-Src
H&E
Phospho-Src Increase at End of
Treatment
Benefit 4/8
Primary resistance
5/6
(P value: 0.05)
Pretreatment End of Treatment
Patient with primary resistance to abiraterone acetate
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Activation of Src kinase signaling in MDA-Pca-133 donor tumor and xenograft
AR Phospho-Src
Donor tumor
AR Phospho-Src
XenograftV. Tzelepi
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0
500
1000
1500
2000
Day 0 Day 12 Day 16 Day 20 Day 24 Day 28 Day 32
Tum
or g
row
th (M
ean
sem
) mm
3
Effect of dastinib, a Src kinase inhibitor, in tumor growth of MDA-Pca-133 xenograft
Control, n=5
Castrated, n=4
Dasatinib, n=5
Cast/Dasatinib, n=4
Days of Dasatinib treatment
J. Song and G. Gallick
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0
500
1000
1500
2000
Day 0 Day 12 Day 16 Day 20 Day 24 Day 28 Day 32
Tum
or g
row
th (M
ean
sem
) mm
3
Effect of dastinib, a Src kinase inhibitor, in tumor growth of MDA-Pca-133 xenograft
Control, n=5
Castrated, n=4
Dasatinib, n=5
Cast/Dasatinib, n=4
Days of Dasatinib treatment
J. Song and G. Gallick
Inhibition of Paracrine AR signaling & interacting ”SE” will enhance efficacy of therapy
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P=0.045
TreatedControl
155.5 mm3 30.5 mm3
MRI
Park, Gallick, Navone
Dasatinib Inhibits Growth of Bone-selected MDA PCA 118b Cells Growing Intratibially
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Osteoclast Function:Dasatinib Inhibits Formation of
Multi-nucleated OsteoclastsM-CSF MCSF + RL
1.25nM
5nM
10nM
20nM
0
500
1000
1500
M-CSF + RL:+ + + + + +
Dasat. (nM): 0 1.3 2.5 5 10 20
TRAP
+ Ost
eocl
asts
/wel
l
Cont.
Araujo and Darnay, unpublished
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Phase 1/2 Dasatinib + Docetaxel Trial on Metastatic Prostate
Dasatinib was administered orally on a once-daily schedule Docetaxel was administered intravenously every 21 days At least three patients were enrolled at each dose level
Continuous daily dasatinib
Day 1
Docetaxel
(PK analysis)
Day 14
(Dasatinib
PK analysis)
Day 21
Docetaxel
(Combination PK analysis)
Day 3
Docetaxel Docetaxel
John Araujo, MD, PhD. PI
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Maximum UNTx change from baseline
Bisphosphonate No bisphosphonate
Max
% C
hang
e fr
om B
asel
ine
BENEFIT
100
80
60
40
0
20
-20
-40
-60
-80
-100
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PSA response curve during and post docetaxel (continued on
Dasatinib)
9/09 Last Docetaxel
19 months on single agent dasatinib with undetectable PSA
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PSA response curve during and post docetaxel (continued on
Dasatinib)
5/09 Last Docetaxel
22 months on single agent dasatinib
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Dasatinib In Castrate Resistant & Metastatic Prostate Cancer
Docetaxel 75 mg/m2 Dasatinib 100 mg po daily Prednisone 5 mg po BID
Docetaxel 75 mg/m2 Prednisone 5 mg po daily Placebo
StratificationPS 0, 1 vs. 2Urinary NTX
RANDOMIZE
mCRPC1st line
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• Chemotherapy• The role of bone • Accelerating progress• Summary advances
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Docetaxel in Castrate Resistant &Metastatic Prostate Cancer
Tannock et al
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Prostate Cancer
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CVD
KAVE
TE+E
TE+C
η = µ +αY + βZ1st
2nd
No.30
30
30
30
120
New Approach
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Regimen+
+
Patientsuccess
∆ to β β
α α
• Rapid selection of most effective regimen
• Arrives to patient success rapidly
+-
+β
Current Practice
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Protocol Allocation Prostate Cancer
TEE KAVE CVD TEC
First Regimen 61 57 48 66Second Regimen 22 13 13 25
TOTAL 83 70 61 91
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Most EfficaciousSequence
CVD (1) TEC (2)
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Beneficial Effect of a “Reasoned” Treatment Approach
Months from initiation of chemotherapy0 20 40 60 80
0.0
0.2
0.4
0.6
0.8
1.0
Taxotere
Serial CHT
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Months from initiation of chemotherapy0 20 40 60 80
0.0
0.2
0.4
0.6
0.8
1.0
Relative Impact of Serial Therapy on Overall Survival
Taxotere vs Mitanzantrone Taxotere vs. Serial chemotherapy*
*simulation
Serial CHT
Taxotere
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Chemotherapy & Castrate Resistant Prostate Cancer
• Castrate Resistant Prostate Cancer is a chemotherapy sensitive Combination(s) may provide advantage
• Serial use of chemotherapy applied based on “principles of cancer therapy”can provide further benefit
• Integration into primary treatment
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Relative Efficacy
Interaction Between
Regimens
Impact Overall Survival
Serial Application of Therapy
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Increased Phospho-Src at Progression More Evident in Patients With Primary Resistance to Abiraterone
Acetate (Preliminary Observations)
P-Src
H&E
Phospho-Src Increase at End of
Treatment
Benefit 4/8
Primary resistance
5/6
(P value: 0.05)
Pretreatment End of Treatment
Patient with primary resistance to abiraterone acetate
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Synergy Between Microenvironment Targeting
Therapies
Abirateroneacetate
RANDOMIZATION
OFF
STUDY
Sunitinib +abiraterone
acetate
Dasatinib +abiraterone
acetate
Sunitinib +abiraterone
acetate
Dasatinib +abiraterone
acetate
Circulating Microenvironment
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T1T2 T3
A+S vs. A+D A+S → A+D
A+D → A+S
Allocation new Rx
Effect of SerialTargeted Therapies
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Relative Efficacy
Interaction
Between Regimen
s
Impact Overall Survival
Link To Biology
Serial Application of Therapy
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Microenvironment pathways implicated in resistance to
maximal androgen ablation are prioritized for individualized
therapy development
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XL184 :Initial Clinical Observations
woven bone
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• Chemotherapy• The role of bone • Accelerating progress• Summary advances
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Androgen Receptor Signaling in Prostate Cancer Involves Multiple Pathways
Growth Factors and Their Receptors
MAPKKK
MAPKK
MAPK
AR
AKTP27
Bad
Caspase9
P13K
PTEN
DHTDHT
5-alpha Reductase(I,II,III)
P P
T T
Li J. and Kim J., 2009
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Dihydrotestosterone
Genetic Networks(anticipated outcome)
DHT
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Cancer Detection in REDUCE by Time, Treatment and Gleason Score
Years 1-2 Years 3-4Placebo Dutasteride Placebo Dutasteride
No. Subjects Biopsied 3345 3929 2342 2446
Gleason 5-6 401 290 216 147
Gleason 7 (3+4) 125 99 51 47
Gleason 7 (4+3) 32 28 6 17
Gleason 8-10 18 17 1 12(0.5%) (0.5%) (0.04%) (0.5%)
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Dihydrotestosterone
Genetic Networks(anticipated outcome)
Androgen Signaling
DHT AR
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ABI
“Earlier” Use of Androgen Biosynthesis Inhibitor
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Didydrotestosterone
Genetic Networks(anticipated outcome)
Androgen Signaling
Microenvironment Dependent
DHT AR NonAR
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“Blast Crisis”
Chronic Myelogenous Leukemia
“Oncogene Addiction”
BCR- ABL
“Microenvironment Dependence”
Androgen Independent Progression
Prostate Cancer
S-E Signaling Network
Elucidating signalingnetwork will lead to
combinatorial microenvironment
targeting
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Autocrine
Paracrine
PhysiologyEpithelial dysregulation
Time
Leth
ality
Che
mot
hera
py re
sist
ance
Proposed Progression Model
Microenvironment Dependence
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Small Cell Carcinoma
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Morphologically heterogeneous Prostate Cancers with clinical features common to small cell carcinomas represent a significant subset of the lethal disease.
The “Anaplastic” Prostate Carcinomas
APARICIO, A. 2009
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“A Phase II Study of Carboplatin plus Docetaxel in Patients with Anaplastic Prostate Carcinoma”
MDA 2006-0097 - PCCTC#c05-015
PSA at Registration
PSA0
20
40
60100150200
3.2
ng/d
L
APARICIO, A. 2009
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DNA Methylation Profiles of the Anaplastic Prostate Carcinomas
ARSCC-1 (MDA 40) SCC-2 (MDA 46)
SCC-3 (MDA 91b) SCC-4 (MDA 144-13)
Xenografts
Sim
ilari
ty
AC-2AC-3AC-4AC-1SCC-3SCC-1SCC-2SCC-4
39.08
59.38
79.69
100.00
Ward Linkage and Absolute Correlation Coefficient Distance
-1,000 +500
APARICIO, A. 2009
AC-1 (MDA 43) AC-2 (MDA 75)
AC-3 (MDA 80) AC-4 (MDA 137)
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Didydro-testosterone
Androgen Signaling Networks (Progression)
AndrogenSignaling
Micro-Environment Dependent
DHT AR NonAR
NonAR
ARInterference
-
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Control Primary
Systemic Therapy
No TherapyControl Primary Systemic
Therapy
MicroenvironmentTargeting
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AcknowledgmentsM. D. Anderson Cancer CenterGenitourinary Medical OncologyW. ArapJ. AraujoA. AparicioP. CornE. EfstathiouG. GallickI. Gorlov
M. Karlou Z. G. LiS. W. LinS. MaityR. MillikanN. NavoneR. PasqualiniP. Sharma
D TsavachidouT. Thompson S.M. TuV. TzelepiX. WanJ. YangA. Zurita
PathologyP. Troncoso
Texas A& M UniversityW. L. McKeehanF. Wang
ImagingV. Kundra
Rice UniversityC. Farach-CarsonInstitute for Molecular MedicineM .Kolonin
UrologyC. PettawayJ. DavisL. Pisters
University of AthensE Efstathiou
NijmegenP. Friedl
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Androgen rich
AR Genomic Signaling
PSA
AR AR
AR
CYP17
AR
Increase steroid biosynthesis
PSA
mAR mAR
mAR
Generation of mutant/isoform AR
SRC/SH2
ARP
P
Cell survival/anti-apoptotic
Non-genomic AR signalingActivation of SRC kinase
Adaptive Response of Androgen Receptor Signaling in CRPC
Castration/Abiraterone treatment