molecular targets for cancer prevention - dr. falk … targets for cancer prevention raymond n....
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Molecular Targets for Cancer PreventionMolecular Targets for Cancer Prevention
Raymond N. DuBois, M.D., Ph.D.Raymond N. DuBois, M.D., Ph.D.Gastroenterology DivisionGastroenterology Division
The VanderbiltThe Vanderbilt--Ingram Cancer CenterIngram Cancer CenterNashville, Tennessee USANashville, Tennessee USA
Falk Symposium 149Falk Symposium 149Berlin, GermanyBerlin, Germany
Epidemiologic Studies of NSAID Use and Colorectal Cancer
Thun MJ et al. Thun MJ et al. J Natl Cancer Inst.J Natl Cancer Inst. 2002;94:2522002;94:252--266.266.
0 0.5 1 1.5 2
Relative Risk
Kune 1988Rosenberg 1991Suh 1993, menSuh 1993, womenPeleg 1994Muscat 1994, menMuscat 1994, womenMuller 1994Reeves 1996Bansal 1996La Vecchia 1997Rosenberg 1998Friedman 1998Coogan 2000, study aCoogan 2000, study b
CyclooxygenaseCyclooxygenase--11
CyclooxygenaseCyclooxygenase--22
Arachidonic AcidArachidonic Acid
PGHPGH22
PGGPGG22
NSAIDs NSAIDs (1(1--55 μμMM))
COXIBsCOXIBsPeroxidasePeroxidase
EPEP11--44 IPIP FPFPDPDPTPTP
PGDPGD22 PGEPGE22 PGIPGI22 PGFPGF22ααTXATXA22
PG SynthasesPG Synthases
COOH
OHOH
O
O
COOHO
OH
COOH
OH
OH
O
COOH
OHOH
OH
OHOH
O
COOH
COOH
OH
O
O
Is COXIs COX--2 a relevant target of NSAIDs 2 a relevant target of NSAIDs which could help explain the which could help explain the decreased risk of colorectal decreased risk of colorectal
adenomas and cancer in humans?adenomas and cancer in humans?
COXCOX--2 Expression in Colorectal Cancer2 Expression in Colorectal Cancer
COXCOX--22
COXCOX--11
N T N TN T N T
1 1 2 2 33
Colorectal Colorectal CancerCancer
Colorectal Colorectal adenomasadenomas
COXCOX--22
COXCOX--11
Eberhart Eberhart et al. & DuBoiset al. & DuBois Gastroenterology Gastroenterology 107, 1183, 1994107, 1183, 1994
Increased COXIncreased COX--2 Expression Is Associated With 2 Expression Is Associated With A Poor Clinical OutcomeA Poor Clinical Outcome
1Sheehan KM et al. JAMA. 1999;282:1254-1257. 2Khuri FR et al. Clin Cancer Res. 2001;7:861-867. 3Ristimäki A et al. Cancer Res. 2002;62:632-635.4Gaffney DK et al. Int J Radiat Oncol Biol Phys. 2001;49:1213-1217.5Buskens CJ et al. Gastroenterology. 2002;122:1800-1807. NSCLC = non-small cell lung cancer
Tumor typeTumor type PrognosisPrognosis P P valuevalue
ColorectalColorectal11 ↓↓ survival ratesurvival rate 0.020.02
NSCLCNSCLC22 ↓↓ survival ratesurvival rate 0.0010.001
BreastBreast33 ↓↓ survival ratesurvival rate 0.00010.0001
CervicalCervical44 ↓↓ survival ratesurvival rate 0.0210.021
EsophagealEsophageal55 ↓↓ survival ratesurvival rate 0.0020.002
Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):616-9.
COX-2 - 765 G > C genotypeOR (95% CI) Cases/Controls
GG (wt) 1.00 (reference) 217/228GC (het) 1.02 90/85CC (hmzyg) 0.26 5/11
The (COX-2) 765G > C promoter variant is located in a SP1 binding site and has been documented to affect COX-2 expression.
Lots of preclinical studies Lots of preclinical studies indicate that COXindicate that COX--2 plays a role in 2 plays a role in
growth and progression of growth and progression of intestinal cancerintestinal cancer
Sheng et al.Sheng et al. J. Clin. Invest., 99, 2254, 1997J. Clin. Invest., 99, 2254, 1997
Williams et al. Cancer Res. 60, 6045, 2000DuBois: Gastroenterology 110, 1259-1262, 1996Kawamori et al. Cancer Res 58:409, 1998
Oshima Oshima et al. et al. CellCell 87, 199687, 1996Jacoby et al. Cancer Res. 60, 1864, 2000Jacoby et al. Cancer Res. 60, 1864, 2000
Tsujii Tsujii & DuBois & DuBois CellCell 83, 199583, 1995 Oshima Oshima et al. et al. EMBOEMBO 23, 166923, 1669--1678 20041678 2004Tsujii Tsujii & DuBois & DuBois CellCell 93, 199893, 1998
COXCOX--2 transgenic mouse studies2 transgenic mouse studies
•• MMTVMMTV--COXCOX--2 transgenic mice were prepared and all 2 transgenic mice were prepared and all develop breast carcinomasdevelop breast carcinomas
•• K19K19--COXCOX--2 transgenic mice develop gastric polyps2 transgenic mice develop gastric polyps
•• COXCOX--2 TG mice in which expression is localized to the 2 TG mice in which expression is localized to the skin have an dramatic increase in skin cancerskin have an dramatic increase in skin cancer
•• Lack of EP1, EP2 and EP4 receptors markedly reduces Lack of EP1, EP2 and EP4 receptors markedly reduces growth and progression of colon tumorsgrowth and progression of colon tumors
Mann JR and DuBois RN, Cancer J. 2004,10, 145.
TGFα, EGF & Other ErbB’s
IL1β
ras, src
Tumor Promoters
COX-2
PGE2
Cell growth Angiogenesis Apoptosis Immune function
LPS
Turini and DuBois Turini and DuBois Annual Rev. of MedicineAnnual Rev. of Medicine 2002;53:352002;53:35--57.57.Gupta and DuBois Gupta and DuBois Nature Rev. CancerNature Rev. Cancer 2001;1:112001;1:11--21. 21.
GastrinHCV
PGEPGE22 Accelerates Adenoma GrowthAccelerates Adenoma Growth
Wang et al. & DuBois: 2004 Wang et al. & DuBois: 2004 Cancer CellCancer Cell; 6, 285; 6, 285--9595
Tota
l Pol
yp N
umbe
r/Mou
seIn
Col
on
Tota
l Pol
yp N
umbe
r/Mou
seIn
Sm
all I
ntes
tine
Vehi
cle 150 300
0
50
100
150
PGE2 (μg)Vehi
cle
150 300
PGE2 (μg)
0
1
2
3
4 9/9(100%)
5/5(100%)
1/9(11%)
Vehicle
PGE2 (150 μg)
300μg+-
Akt
+-150μgPGE2
P-Akt
Colon
Vehicle PGE2(150 μg)
PGE2 Affects Cellular Organization
c d
PGEPGE22 (100 nM) (100 nM) Control Control
MucinMucin
Sheng et al. J. Biol. Chem. 276, 18075, 2001
PGE2 Affects Cell Migration & Invasion
Cell Number
10
20
30
40
Control PGE2
Sheng et al. J. Biol. Chem. 276, 18075, 2001
10
30
50
60
Control PGE2
40
20
Migration Invasion
Buchanan et al. J. Biol. Chem. 278, 35341, 2003
Important interactions between PGE2receptors and Arrestin
EP Activation and CRC Metastasis
Celecoxib FAP Phase II TrialSubjects with FAP (83)
Randomize to celecoxib treatment or placebo
Baseline evaluation: endoscopy, APC mutations, biopsies
6 month evaluation
Endpoint: Polyp number & size
Steinbach: NEJM 342, 1946, 2000
Percent Change in Colorectal Polyp Burden
* P = 0.001
-40
-35
-30
-25
-20
-15
-10
-5
0
Placebo- 4.9%
100 mg BID-14.6%
400 mg BID*-30.7%
N=15 N=32 N=30
% Change from Baseline
Mean ± SEM
Steinbach: NEJM 342, 1946, 2000
Before treatment
After treatment
Serum Proteomic Profiles Suggest Celecoxib-Modulated Targets and Response Predictors
Xiao et al: Cancer Res 64, 2904, 2004
Strong Responders
Non-Responders
RANDOMIZE
celecoxib 400 mg QD
placebo
RANDOMIZE
celecoxib 400 mg BID
placebo
200 mg BID
PreSAP – 1561 patients
APC – 2035 patients
AdenomaFree
2000 2005 2007
No
Year 1 Colonoscopy
Year 3 Colonoscopy
SAP Study Design
3 Years
Stratified by low-dose aspirin use
Stratified by low-dose aspirin use
Yes Continue Blinded Rx
Off-Rx FU
Year 5 Colonoscopy
Year 5 Colonoscopy
- durability- long-term
safety
- Follow Up colonoscopies
PRIMARY END POINT Occurrence of newly detected adenomas
2 Year Extension
DeclineDeclineParticipationParticipation
Are longAre long--term use of these term use of these inhibitors safe in humans?inhibitors safe in humans?
Symptoms of withdrawal: Loss of arthritis drug adds to group’s woes
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APPROVe Confirmed Thrombotic Events
0 6 12 18 24 30 36
Patients at riskPlacebo
Rofecoxib 25 mg1299 1192 1148 1079 1039 1002 4701287 1123 1050 986 935 898 411
0
2
4
6
8
CummulativeIncidence (%)
Months
Bresalier et al. (2005) NEJM 352, 1092-1102
Rofecoxib
Placebo
Observed ~ 25% reduction in polyp recurrenceObserved ~ 25% reduction in polyp recurrence
Celecoxib and Cardiovascular Events
Solomon SD, et al. NEJM 352, 2005
A European trial of similar design showed no difference in cardiovascular side effects between placebo and 400 mg of celecoxib (daily dose)
*In this analysis, “serious CV events” include death from CV causes, MI, stroke, or heart failure
671
Solomon SD, et al. NEJM 352, 2005
Kaplan-Meier Estimates of the Risk of Serious CV Events in the APC Trial by Treatment Arm*
681 676 675 673 670 611669 665 655 651 648 594677 675 672 668 667 612
Months sincefirst dose
Sample size
C 200 BIDC 400 BIDPlacebo
Log-rank statistic 8.74 (p= 0.013)
E:\Proj\APC Cox2\Programs\f KMplot.sas v.010 death MI stroke CHF 005 01.cgm (last run: 02/14/2005, 10:46CEC adjudication data (received 02/03/2005) RAND data (received 11/23/2004) CRF data (received 02/03/2005)
Est
imat
ed p
roba
bilit
y of
CV
dea
th, M
I, st
roke
, or
CH
F
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
6 12 18 24 30 36
Kaplan-Meier Estimates of the Risk of Serious CV Events in the APC Trial by Treatment Arm
PlaceboPlacebo200 mg bid200 mg bid
400 mg bid400 mg bid
COXCOX--2 selective inhibitors will no 2 selective inhibitors will no longer be evaluated in patients at longer be evaluated in patients at
low risklow risk for cancer.for cancer.
What is responsible for increased What is responsible for increased cardiovascular risk?cardiovascular risk?
SummarySummary•• COXCOX--2 levels are increased in colorectal carcinomas and its 2 levels are increased in colorectal carcinomas and its
expression is affected by numerous factorsexpression is affected by numerous factors
•• LongLong--term use of term use of celecoxib celecoxib (800 mg per day) has adverse (800 mg per day) has adverse effectseffects
•• Downstream signals in the COXDownstream signals in the COX--2 pathway (PGE2 pathway (PGE22) may also ) may also serve as useful targets for cancer preventionserve as useful targets for cancer prevention
•• Personalized medicine approaches may reveal those who Personalized medicine approaches may reveal those who would benefit most from treatment with COXwould benefit most from treatment with COX--2 selective 2 selective inhibitorsinhibitors
• Dingzhi Wang• Yong Cha• Jason Mann• Yuko Kino• Pranathi Matta• Sharada Katkuri• Greg Buchanan• Suzy Wilkinson• Shi Qiong• Vijay Holla
• R. Daniel Beauchamp (VUMC)• Jason Morrow (VUMC)• Kay Washington (VUMC)• Larry Marnett & Lab (VUMC)• S.K. Dey & Lab (VUMC)• Masahiko Tsujii (Osaka U.)
DuBois Laboratory Others
Acknowledgements