Targeting The Stress-Induced Cytoprotective Chaperone, Clusterin, to Overcome Treatment Resistance in Advanced Prostate Cancer Martin Gleave MD, FRCSC, FACS Professor, Department of Urologic Sciences University of British Columbia B.C. Leadership Chair in Prostate Research Director, The Prostate Centre at VGH Disclosure of Conflicts of Interest Patent - OGX-011 Founder - OncoGenex Technologies Consultant - CSO, OncoGenex Technologies
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Targeting The Stress-Induced Cytoprotective Chaperone ...Targeting The Stress-Induced Cytoprotective Chaperone, Clusterin, to Overcome Treatment Resistance in Advanced Prostate Cancer
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Targeting The Stress-Induced Cytoprotective Chaperone, Clusterin, to
Overcome Treatment Resistance in Advanced Prostate Cancer
Martin Gleave MD, FRCSC, FACS
Professor, Department of Urologic SciencesUniversity of British ColumbiaB.C. Leadership Chair in Prostate ResearchDirector, The Prostate Centre at VGH
Disclosure of Conflicts of InterestPatent - OGX-011Founder - OncoGenex TechnologiesConsultant - CSO, OncoGenex Technologies
NCIC IND.165: Taxotere +/- OGX-011 in First-Line mHRPC
Chi et al, ASCO, 2007
NCIC IND.165: Taxotere +/- OGX-011 in First-Line mHRPC
Median for Arm A (OGX-011 + Docetaxel): 7.26 months (95%CI 5.22-9.33)Median for Arm B (Docetaxel): 5.85 months (95% CI 3.61-10.74)
At Risk0
20
40
60
80
100
Arm A: OGX-011 + DocetaxelArm B: Docetaxel
0.04041
5.02118
10.024
15.000Arm B
Arm A
Time (months)
Mature Data
Progression Free Survival
Chi et al, ASCO, 2007
Indicators of Anti-cancer Activity
Consistent trend in favor of OGX-011/docetaxel arm:More patients with a 50% decline in PSA within the first 12 weeks More pts (38% vs 22%) with >80% decline in PSA; less pts (0 vs 10%) with primary PSA progression as best response Longer time on treatment and a greater median # of treatment cycles.Higher frequency and longer duration of stable measurable disease.Lower frequency of progressive disease as “best response”. Longer time to progression
NCIC IND.165: Taxotere +/- OGX-011 in First-Line mHRPC
Cel
l pro
lifer
atio
n
0
20
40
60
80
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120
0 15 31 63 125 250 500 1000
PC3-R MM
PC3-R ASO
PC3 MM
PC3 ASO
OGX-011 in docetaxel-refractory HRPC:CLU knockdown chemosensitizes taxane-resistant PC3-dR cells to docetaxel
docetaxel +/- OGX-011
0
20
40
60
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100
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0 15 31 63 125 250 500 1000
PC3-R MM
PC3-R ASO
PC3 MM
PC3 ASO
CLUVinculin
PC-3
PC-3R
MM OGX01150 200 500 50 200 500 O
onl
y
CLUVinculin
In vitro Docetaxel concentration (nM)
-0.5
0
0.5
1
1.5
2
2.5
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3.5
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1 2 3 4 5 6 7 8 9
weeks
PC-3R, MM
PC-3R, OGX-011
PC-3, MM
PC-3, OGX-011
* *
In vivo
* - chemotherapy treatment
Tum
or V
olum
e
Phase II Feasibility Trial of OGX-011 in 2nd Line Therapy in HRPC:
RANDOMIZE
Arm ADocetaxel (75 mg/M2 IV) q 21 days and OGX-011 (640 mg IV) weekly plus Prednisone (5 mg po bid) daily
Arm BMitoxantrone (12 mg/M2 IV) day 1 and OGX-011 (640 mg IV) weekly plus Prednisone (5 mg po bid) daily.
Continue treatment until disease progression or unacceptable toxicity. If removed from treatment for any reason, follow until death
PR
D OI G
S RE EA SS SE I
ON
S FU OR LV LI OV WA L U
P
n = 41
HRPC Patients Who Had Disease Progression
During or Within 6
Months of 1st
Line Docetaxel Treatment
n = 19
n = 22
Study treatment ongoing in 11 (26%) of patients
OGX-011 in 2nd Line Therapy in HRPC:Chemosensitizes taxane-resistant patients to docetaxel
0
500
1000
1500
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4500
PSA
Valu
e
Start 1st line therapy
End 1st line therapy6 cycles
Start 2nd line therapy
Off Study Treatment for disease progression
5 Cycles
Time (2 Weeks per mark)
Patient: 009-002
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Time (2 Weeks per mark)
PSA
Valu
e
Off Study Treatment for
disease progression
6 cycles
Start 1st line therapy
End 1st line therapy5 cycles
Bone Scan, PSA Progression
Start 2nd line therapy
Patient: 025-002
Summary: Clusterin as a Therapeutic Target in HRPC
sCLU is a stress-activated cytoprotective chaperone that is highly expressed in HRPC
Over-expression of sCLU-2 confers broad spectrum treatment resistanceInhibits protein aggregation, facilitates proteasome degration of ubiquitinated proteinsInteracts and and inhibits activated Bax, preventing cytochrome C releaseIncreases NF-kB transcriptional activity
CLU knockdown using OGX-011Enhances treatment-induced apoptosis in vitro and in vivoPre-clinical proof-of-principle in prostate, breast, lung, urothelial, melanoma, renal cell
OGX-011, a 2nd generation ASO potently suppresses target CLU levels >90% in human CaP tissues
Anti-cancer activity observed in multi-centre Phase II trials in breast, HRPC, lungPhase III registration trial in second-line HRPC set to begin in 2008
++ PSA- Bcl-2
- EGFR- clusterin
- IGFBP 2&5- TGFβ
++IGFBP 3 & 4-YB-1
++survivin-Hsp27
+ PKC-α
- PSA++ Bcl-2++Bclx-L- EGFR
+++ clusterin++++IGFBP 5IGFBP 3 & 4
+c-myc+YB-1
-survivin+Hsp27
+ PKC-α
++ PSA++ Bcl-2++Bclx-L+ EGFR
+++ clusterin++ IGFBP 2++ IGFBP 5
++YB-1++ survivin+++Hsp27
Changes in Gene Expression After Castration Changes in Gene Expression After Castration and During AI Progression and During AI Progression
Androgen-dependent
Tumour regression
Androgen-independent
Clonal selectionAdaptive responses
Hormone withdrawal Progression
AI
ADAI AI
Post-docs
Hide MiyakeMoto Muramaki
Isis PharmaceuticalsBrett Monia
PI’sKim ChiLarry GoldenbergColleen Nelson Paul RennieAlan So
Sue EttingerAmina Zoubeidi Eliana BeraldiRichard SoweryPathology
Antonio HurtadoLadan Fazli David HuntsmanTorsten NeilsenTed Jones
Grant FundingNCICNIH SPOREDoDPCF
CollaborationsUW - B. VessellaP. Lange, P Nelson, Tia HiganoU Montreal - F. Saad
OncoGenex Tech. Inc.Scott Cormack
NCIC IND GroupElizabeth EisenhauerLesley Seymour
OGX-011: Safety Profile in >270 Patients
Well tolerated in all Phase 1 and Phase 2 studies to date Safety profile of OGX-011 in combination with docetaxel vsdocetaxel alone
Increase in Grade 1 or 2 AE’s events (fever, rigors/chills and sweating during the loading-dose week and sensory neuropathy during therapy)lymphopenia was more prevalent in the OGX-011 + docetaxel arm (no clinical sequelae)No increase in SAEs in the OGX-011 + docetaxel arm
OGX-011 in combination with gemcitabine/platinum-based or mitoxantrone regimens
Safety profile similar to that expected for regimen (no increase in expected rate of Grade 3 or higher AEs)
OGX-011 Mechanism of Action
OGX-011
↑ nCLU
⇑ Cytochrome C ↓ NF-κB ⇑ ER Stress ↓ ProteasomeActivity