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1
Prostate Cancer and 2Prostate Cancer and 2°°ChemopreventionChemoprevention
Ralph W. de Vere White, MDRalph W. de Vere White, MDDirector, UC Davis Cancer CenterDirector, UC Davis Cancer Center
Associate Dean for Cancer Programs Associate Dean for Cancer Programs Professor, Department of UrologyProfessor, Department of Urology
Definition of 2Definition of 2 ChemopreventionChemoprevention
Diagnose the disease Diagnose the disease
Then use non toxic intervention to:Then use non toxic intervention to:
–– Slow disease progressionSlow disease progression
–– Stop disease progressionStop disease progression
–– Eliminate diseaseEliminate disease
All without increasing the chance of dying All without increasing the chance of dying from the diseasefrom the disease
2
While Waiting to Cure Prostate While Waiting to Cure Prostate Cancer Cancer
Maximize ScreeningMaximize Screening
Increase PreventionIncrease Prevention
Prostate Cancer Ideal Target for Prostate Cancer Ideal Target for ChemopreventionChemoprevention
Long natural history Long natural history
One doubling = 7 yearsOne doubling = 7 years
High prevalenceHigh prevalence
200,000 men diagnosed200,000 men diagnosed
30,000 men die (2005)30,000 men die (2005)
3
Problems with Primary PreventionProblems with Primary Prevention
Required time of exposureRequired time of exposure
Personal choices Personal choices –– (smoking, diet)(smoking, diet)
Expense diet/pillsExpense diet/pills
One plan will not fit allOne plan will not fit all
Worry about side effectsWorry about side effects
How to prove it worksHow to prove it works
PCPTPCPT
Need to treat 71 healthy men for 7 Need to treat 71 healthy men for 7 years to prevent one case of CaP. Of years to prevent one case of CaP. Of these cases, 50% will be low risk.these cases, 50% will be low risk.
4
How to Solve a ProblemHow to Solve a Problem
Start with 2Start with 2 chemopreventionchemoprevention
–– More likely to be acceptedMore likely to be accepted
–– Quicker to prove it worksQuicker to prove it works
–– Considerably less expensiveConsiderably less expensive
CardiopreventionCardioprevention
StatinsStatins
AntihypertensivesAntihypertensives
AsprinAsprin
5
Has PSA Saved Lives?Has PSA Saved Lives?
YES!!YES!!
Prostate Cancer Death RateProstate Cancer Death Rate
Population growth 11%Population growth 11%
24% Drop in per capita death rate24% Drop in per capita death rate
Fortune 11/21/04
Death Death Year Year
34,90034,900 19931993
29,00029,000 20042004
27,56027,560 20062006
6
PSA: Stage MigrationPSA: Stage Migration
Pre PSAPre PSA Post PSAPost PSA
D2 at RXD2 at RX 30%30% 3%3%
Node Positive 22%Node Positive 22% 2%2%
Margin Positive 30%Margin Positive 30% 15%15%
T1CT1C 10%10% 84%84%
PSA Screening:PSA Screening:Opportunity for 2Opportunity for 2oo ChemopreventionChemoprevention
Predictions of National Incidence and MortalityProstate Cancer
1984 1986 1988 1990 1992 1994 1996 1998 2000 2002
Year
0
100
200
300
400
500
600
700
800
900
Age-a
dju
ste
d in
cid
ence p
er 100,0
00 m
en o
ver 50
0
40
80
120
160
200
240
280
Age-a
dju
ste
d m
ortality p
er 100,0
00 m
en o
ver 50
Incidence: Observed Mortality: Observed Mortality: UCD Model prediction Mortality: UCD Model prediction w/o PSA
Tsodikov
T1C 10% 84%
7
At the Time of Diagnosis in the At the Time of Diagnosis in the U.S. and in EuropeU.S. and in Europe
50% of Prostate Cancers are no 50% of Prostate Cancers are no immediate threat to the patient immediate threat to the patient
“Insignificant CaP”
Opportunity for 2Opportunity for 2˚ Chemoprevention˚ Chemoprevention
Maximize benefits from screeningMaximize benefits from screening–– Lives savedLives saved
Minimize risks from screening Minimize risks from screening –– Over treatmentOver treatment
Make surveillance active therapy Make surveillance active therapy
8
Rational for Active SurveillanceRational for Active Surveillance
Over Treatment of Prostate CancerOver Treatment of Prostate Cancer
Incidence of CaP Incidence of CaP 170/100,000170/100,000
Die from CaP Die from CaP 32/100,00032/100,000
Die of something elseDie of something else 138/100,000138/100,000
Active SurveillanceActive Surveillance
## Median FUMedian FU WithdrawWithdraw
*206*206 29 Months29 Months 33%33%
**81**81 23 Months23 Months 31%31%
*Choo, R J Urol 2002, (167)1664-1669
**Carter HD, J Urol 2002, (107) 1231-1234
8% of Men suitable for Active Surveillance go on it (Capsure)
9
#1 Pre Study #2 Pre Study Baseline 6 Mo
PSA
PSAPSA PSA
PSA Tests
AHCC Study
PSA
4 Mo
AHCCAHCC
AHCCAHCC
Final Patient StatusFinal Patient StatusCRCR 0/610/61
PRPR 0/610/61
StableStable 4/61 (7%)4/61 (7%)
ProgressedProgressed 23/6123/61
PUBLICATIONSEffects of a Mushroom Mycelium Extract on the Treatment of Prostate Cancer. Urology 60 (4), 2002.
10
GCP a GenisteinGCP a GenisteinGCP a GenisteinGCP a Genistein----Rich Compound Rich Compound Rich Compound Rich Compound The Road from Bench to BedsideThe Road from Bench to BedsideThe Road from Bench to BedsideThe Road from Bench to Bedside
Ralph W. deVere White, M.D.Ralph W. deVere White, M.D.Ralph W. deVere White, M.D.Ralph W. deVere White, M.D.Assistant Dean of Cancer Programs Director, UC Davis Cancer Center Professor, Department of Urology University of California, Davis Medical Center
GCP (Genistein Combined Polysaccharide)
“GCP is a natural anti-tumor substance containinglegumenous isoflavones and basidiomycetes polysaccharide.”
“GCP is produced by a special soybean fermentation technique involving isoflavone extracts and medicinalmushrooms.”
“Isoflavone glycosides are transformed into aglycones usingb-glucosidase producing basidomycetes using an innovativeJapanese technology.”
11
Genistein Content in Soyfoods Genistein Content in Soyfoods and GCPand GCP
0.55 0.05 0.16
92.8
0
50
100
Concentration
mg/g
Soybeans
Soymilk
Tofu
GCP
Zyo-Kyo 90:592-6, 1995New Food Industry 40:59-64, 1998
Serum Serum DaidzeinDaidzein ConcentrationConcentrationin Men with Prostate Cancerin Men with Prostate Cancer
0
4000
8000
Conc
ng/ml
Jpn J ClinOncol 2002
UC DavisStudy
35.735.735.735.7
6,347
178x178x178x178x
12
Genistein Combined Polysaccharide (GCP)Effects in Prostate Cancer
Led to ongoing double-blind randomized trial in patients on active surveillance with prostate cancer (2o chemoprevention)
PC3 Xenografts Human Study
P=0.002
0
20
40
60
80
100
120
140
160
180
0 5 8 12 15 19 22 26 29 31 33 36 40 43 47 50
Days after inoculation
Control
GCP
Days after inoculation
Tu
mo
r S
ize (
mm
3)
Percent change in 6 month PSA over baseline PSA by treatment
Active Surveillance
Increased p21, p27Decreased VEGFTUNEL +
G C P vs . P laceb o in A c tive S u rve illan c e
R eg istra tio n
R a n d om iz a tio n (D ou b le -B lin d )
G C P x 6 M o n ths P lac eb o x 6 M o n th s
Init
ial
Ph
ase
(0-6
mo)
Cro
sso
ver/C
on
tin
uati
on
(6-1
2 m
o)
Lo
ng
-term
(>1
2 m
o)
P S A P S A P S AP S A
A ll p a t ien ts u nb lind ed a t 6 m on th s
O F F ST U D Y (N o F ree G C P )
P S A In c re ase
P S A D ecrease
P S A Stab le
O F F ST U D Y (Fre e G C P )P S A M an d a tory ev ery 6 m o b y P C P u n ti l PS A
F r ee G C P x 6-1 2 M o nth s(J o in t D o c to r /P a tie nt D ec is ion )
P S A M and ato ry a t 9 and 1 2 m o
P S A P S A
Completed GCP Clinical Trial
13
53 Participants Completed Baseline and 6 Month PSA Assessment
# of Pts# of Pts GroupGroup Mean AgeMean Age RangeRange Gleason Gleason ScoreScore
22--4 54 5--7 87 8--1010
2525 PlaceboPlacebo 68.668.6 52.852.8--80.680.6 3 22 03 22 0
2828 GCPGCP 70.570.5 51.051.0--86.286.2 0 27 10 27 1
13 Participants OFF-STUDY Prior to 6 Month PSA Assessment
# of Pts# of Pts Adverse EventAdverse Event
77 DiarrheaDiarrhea
11 Skin RashSkin Rash
22 Other TherapyOther Therapy
22 Unrelated Medical IssueUnrelated Medical Issue
11 Too Many CapsulesToo Many Capsules
1313 TOTALTOTAL
14
Absorption of GCP
19 / 20 Caucasians
0 / 3 African-Americans
1. 0 0
10 . 0 0
10 0 . 0 0
10 0 0 . 0 0
10 0 0 0 . 0 0
10 0 0 0 0 . 0 0
10 0 0 0 0 0 . 0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 2 0 2 1 2 2 2 3
Pat ient s
GCP Patients % GENISTEIN CHANGE (Base to 6 Mo)
15
PSA RESPONSE at 6 MONTHSPSA RESPONSE at 6 MONTHS
STABLE / STABLE / REDUCTIONREDUCTION
INCREASEDINCREASED
TotalTotal >20% >20%
decrease*decrease*TotalTotal >20% >20%
increase*increase*
## %% ## %% ## %% ## %%
GCPGCP 14/2814/28 5050 3/283/28 1111 14/2814/28 5050 6/286/28 2121
PlaceboPlacebo 8/258/25 3232 1/251/25 44 17/2517/25 6868 7/257/25 2828
4 Participants Biopsied Post GCP
3 of 4 pT0
16
Question that study raises:
Is 6 Month GCP Long Enough?
YES* Katz: 6 wks GCP, 1.5 gm Daily, PSA 19.7 ng/mL to 4.2
ng/mL at Radical Prostatectomy (p0)
*,**
** Schröder: 49 pts 10 wks of nutrients PSADT 445 to 1150 Days
Is PSA / PSADT Valid Surrogate?
• Worked For Others
• Standard for Active Surveillance Studies
17
Role of Prostate Biopsies
3 of 4 of our cases were pT0
• Due to affect of GCP?
• Missed by biopsy?
HOWEVER If no evidence of progression on biopsy, should GCP be stopped?
Can CGP be Made More Effective?Can CGP be Made More Effective?
Does Basic Science Data Support Does Basic Science Data Support Continued Use of GCP?Continued Use of GCP?
18
PROSTATE CANCER CELLSPROSTATE CANCER CELLSAFTER ANDROGEN WITHDRAWALAFTER ANDROGEN WITHDRAWALINITIATE MOLECULAR SURVIVAL INITIATE MOLECULAR SURVIVAL
PROGRAMPROGRAM
KEYKEY
Blocking Initial Survival Blocking Initial Survival Increasing ApoptosisIncreasing Apoptosis
LNCaP, Fetal Bovine Serum
Counted Day Three
0
20
40
60
80
100
120
0 50 100 150 200 250
ug/ml GCP
% C
ha
ng
e i
n C
ell
N
um
be
r
100
LNCaP, Fetal Bovine Serum Counted Day Three
19
Increasing Apoptosis after Increasing Apoptosis after Androgen WithdrawalAndrogen Withdrawal
LNCaP grown in androgenLNCaP grown in androgen--deprived deprived media: media: 55--15%15% apoptosisapoptosis
Addition of phosphoAddition of phospho--AKT inhibitor AKT inhibitor (wortmannin) increases apoptosis to (wortmannin) increases apoptosis to ~75% (~75% (WM: 100nM; LY: 1uM)WM: 100nM; LY: 1uM)
Goal is to achieve the maximum Goal is to achieve the maximum degree of apoptosis with an degree of apoptosis with an acceptable sideacceptable side--effect profileeffect profile
LNCaP cells
subG1: 17.93%
GCP
subG1: 5.42%
Vehicle
LNCaP-R273H
Vehicle
subG1: 3.23%
GCP
subG1: 11.24%
LY294002
subG1: 14.12%
LY + GCP
subG1: 48.97%
LNCaP
GCP Induces Apoptosis
20
Can we in Patients Safely Block Can we in Patients Safely Block P. AKTP. AKT
Yes Yes
PerifosinePerifosine
0
25
50
75
100
125
0 20 40 60 80 100 120
Perifosine (uM)
% G
row
th
LNCaP-R273H, CSS
LNCaP-R273H
0
25
50
75
100
125
0 20 40 60 80 100 120
Perifosine (uM)
% G
row
th
C42, CSSC4-2
0
25
50
75
100
125
0 20 40 60 80 100 120
Perifosine (uM)
% G
row
th
LNCaP, FBSLNCaP
0
25
50
75
100
125
0 20 40 60 80 100 120
Perifosine (uM)
% G
row
th
PC3, CSSPC-3
0
25
50
75
100
125
0 20 40 60 80 100 120
Perifosine (uM)
% g
row
th
LNCaP, myrAkt
Perifosine ICPerifosine IC5050
LNCaP, FBS, 72hLNCaP, FBS, 72h ~8uM~8uM
LNCaP, FBS, 72hLNCaP, FBS, 72h ~22uM~22uM
C42, CSS, 72hC42, CSS, 72h ~64uM~64uM
PC3, CSS, 24hPC3, CSS, 24h ~1uM~1uM
Perifosine IC50 Values; Myristoylated Akt can prevent perifosine-induced growth inhibition in LNCaP.
A B
C D
E F
21
0
20
40
60
80
100
120
vehicle
GCP
perif
osine
G+P
vehicle
GCP
perif
osine
G+P
vehicle
GCP
perif
osine
G+P
vehicle
GCP
perif
osine
G+P
vehicle
GCP
perif
osine
G+P
% C
olo
ny F
orm
ati
on
LNCaP R273H C42 cds1 PC3
Clonogenic Assay; as single agents GCP and perifosine can inhibit Growth. In combination growth is further inhibited.
PARP
B-actin
Veh GCP peri G+P veh GCP peri G+P
FBS CSS
LNCaP
Cleaved PARP
PARP Cleavage; Confirmation that treatment with a combination
of GCP and Perifosine increases levels of apoptosis.
22
MECHANISM OF ACTION
MECHANISM OF ACTIONMECHANISM OF ACTION
P-Akt
B-actin
Total Akt
Veh GCP peri G+P
Phospho p70S6K
B-actin
veh GCP peri G+P
Total p70S6K
1. Increased inhibition
of Akt activity.
2. Increased inhibition of
mTOR activity.
23
GCP Antagonizes Androgen Receptor Signaling
GCP diminishes AR-dependent gene expression
GCP treatment markedly down-regulates AR levels
PSA RT-PCRVeh GCP -ve
AR
PSA
B-actinveh GCP veh GCP
FBS CDT-FBS
AR
B-actin
0
100
200
300
400
500
600
700
800
vehicle GCP perifosine G+P
ng
/ml
PS
A
control siRNA
AR siRNA
MECHANISM OF ACTION
0%10%20%30%40%50%60%70%80%90%
100%
ve
hic
le
GC
P
pe
rifo
sin
e
G+
P
ve
hic
le
GC
P
pe
rifo
sin
e
G+
P
control si AR si
Ce
ll C
yc
le
G1
S
G2
subG1*** ***
******
3. Simultaneous inhibitionof Akt activity AND ARPathway.
24
Is Effect of GCP Seen Only Is Effect of GCP Seen Only With Androgen Withdrawal?With Androgen Withdrawal?
Figure 1 Day 2A
B
0
100000
200000
300000
0.0
0.1
0.2
0.3
0.4
0.5
*
*
*Apoptosisnormalized to cellnumber
MTT
OD
Day 2
RF
U/O
D
Active Caspases 3 and 7 measured using a flourescent plate reader. Normalized to cell numbers
25
1 U
ntr
eate
d2 G
CP
3 D
oceta
xel
4 B
icalu
tam
ide
5 pp2
6 G
CP
+
Doceta
xel
7 G
CP
+
Bic
alu
tam
ide
8 G
CP
+ p
p2
LNCaP lysates
PARP
β-actin
Cells Harvested at 24 hours post treatment
PARP
1 U
nt
2 G
CP
24
3 G
CP
48
4 D
oceta
xel 24
5 D
oceta
xel 48
6 D
oceta
xel to
GC
P
7 G
CP
to D
oceta
xel
8 G
CP
+ D
oceta
xel
pAKT
AKT
p21
β-actin
LNCaP harvested day 3.
InPress BJU, Burich, RW de Vere White, Mack, P.
26
Dutesteride Vs. Dutesteride + GCP + Perifosine in Patients on Active Surveillance for Prostate Cancer.
Randomization
ARM 1 ARM 2
Dutesteride X 9 Months Dutesteride + GCP +
Perifosine X 9 Months
OFF TREATMENT at 9 Months
Prostate Biopsy at 12 Months (All Patients)
PSA at 18 + 24 Months
OFF STUDY Endpoints: PSA, PSA Velocity, Biopsy Path,
Subsequent Therapy
deVere White
Lab