Transcript Prostate cancer

The Emerging Role of
Bisphosphonates in the Early
Treatment of Prostate Cancer
Carlos Rabaça
IPOFG Coimbra
FMUC
XIV WORKSHOP DE UROLOGIA ONCOLÓGICA
Carvoeiro, 22-23 de Outubro de 2010
1
Prostate Cancer Epidemiology
•
Most common cancer in men
•
High rate of diagnosis in industrialized nations because of
testing for prostate-specific antigen (PSA)
– PC often diagnosed in early stages, allowing for early treatment
– Prognosis is worse for other regions and for some ethnic groups
(2007 data)
New cases, n
Demographics - Location
Developed countries
Underdeveloped countries
a
Prostate cancer incidence
General
prognosis
782,600
—
~75% of diagnoses
~25% of diagnoses
Favorablea
Poor
Survival may be relatively low in countries with conservative versus active management practices.
PC, prostate cancer.
American Cancer Society. 2007.
Treatment Recommendations for Patients
With Prostate Cancer
Early Stage
T1a
• Active
surveillance
• Brachytherapy
• Surgery
• Radiation
• LHRH analogue
• Combination
•
•
•
•
Recurrent/Metastatic
HSPC
CRPC
Salvage radiotherapy
• Chemotherapy
LHRH analogue
• Zoledronic acid
Orchiectomy
• Radiation
Combined androgen
• Radio-pharmaceuticals
blockade
• New agents
T4
HSPC, hormone-sensitive prostate cancer; CRPC, castration-resistant prostate cancer; LHRH, leutinizing hormone releasing hormone.
Note: palliative therapies are not included in this list.
Heidenreich A, et al. Eur Urol. 2008;53(1):68-80.
Would CRPC Therapies Be Beneficial in Earlier
PC Settings?
Phase III trials of docetaxel in adjuvant/neoadjuvant PC
Principal investigator
Local
treatment
No. patients
(enrolled/planned)
Status
GETUG 12
K. Fizazi (France)
XRT
413 / 400
Accrual completed
RTOG 0521
H. Sandler (USA)
XRT
260 / 600
Ongoing
M. Eisenberger (USA)
RP
228 / 1,700
Early enrollment
termination
AdPro
Ahlgren (Sweden)
RP
154 / 396
Ongoing
DOCET-L-02357
A. D’Amico (USA)
XRT
100 / 350
Ongoing
VA # 553 CAP
Montgomery (USA)
RP
65 / 636
Ongoing
CALGB 90203
Eastham (USA)
RP
14 / 750
Ongoing
Kellokumpu-Lehtinen (Fin)
XRT
9 / 924
Ongoing
Study name
TAX 3501
AdRad
CRPC, castration-resistant prostate cancer; PC, prostate cancer; XRT, external-beam radiotherapy; RP, radical prostatectomy.
Fizazi K, personal communication; Mazhar D, et al. Nat Clin Pract Urol. 2008;5(9):486-493.
Bisphosphonates
Effects in Bone
Bisphosphonates reduce tumour burden in
bone in a range of different cancer types.
A result of direct and indirect effects targeting both tumour and the bone
microenvironment.
Effects on Tumours Outside of Bone
Can BPs also affect tumour growth outside
bone?
How?
Bisphosphonates Can Inhibit Several
Key Steps of the Metastatic Cascade
Primary tumor
Angiogenesis
Intravasation
Inhibits
angiogenesis
Stimulates immune
surveillance
Induces
tumor cell
apoptosis
Inhibits bone
resorption
Metastases
Decreases
adhesion to
bone
?
Decreases
matrix invasion
Adhesion &
extravasation
Arrest in distant
capillary
Indirect antitumor effect
Direct antitumor effect
Micrometastases
Adapted from Mundy GR, et al. Nat Rev Cancer. 2002;2(8):584-593.
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How Can Tumour Growth in Bone be Reduced by BPs?
Induce apoptosis of tumour cells
BP
Tumour cells
Tumour/bone
microenvironment:
Macrophages
Immune cells
Fibroblasts
Stromal cells
Endothelial cells
Bone marrow precursors
Adipocytes
Osteoblasts
BP
Osteocyte
Reduce release of bone-derived
tumour growth factors
Potentially exerts
anticancer effects
on a range of
additional cell
types involved in
tumour
development
???
Osteoclast
Induce apoptosis of osteoclasts
BP
Can Bisphosphonates Inhibit Several Key Steps or
Cellular Components of the Cancer Niche?
 Disseminated tumor cells (DTCs)
 Osteoclast and macrophages
 Osteoblasts
 Bone Marrow Stromal cells
 CEP and CEC
Cancer stem cell niche
 Gamma/delta () and alfa/beta T cells
 MSC (Mesenchimal Stem Cells)
 HSC VEGFR1 or 2 pos
 Cancer Stem Cells
8
Disseminated Tumor Cells
Cancer stem cell niche
Lin et al
ASCO 2008
Zoledronic acid
4 mg/month × 1 year
77%
Reduced BM
micromets at
1 year
N = 45 with BM micromets
after adjuvant chemotherapy
N= 31
Zoledronic acid 8 mg,
then 4 mg/month × 6 months
Rack et al
2008
N = 172 with BM
micromets after
adjuvant chemotherapy
N= 141
No zoledronic acid
13%
Persistent BM
micromets at
39 months
27%
Persistent BM
micromets at
39 months
9
Antitumour Effect of Amino Bisphosphonates
- Potential Mechanism
Reduced release of proteolytic
enzymes (MMP-9) from tumour
macrophages
Reduced release of VEGF from the extracelluar matrix
VEGF levels too low to signal mobilisation of
hematopoietic stem cells from the bone marrow
Treated
tumour
Control
tumour
Reduced tumour angiogenesis
and growth
Coscia M, et al. J Cell Mol Med. 2009 Oct 10. [Epub ahead of print].
Melani C, et al. Cancer Res. 2007;67(23):11438-11446.
Giraudo E, et al. J Clin Invest. 2004;114:623-633.
Reprinted from Ottewell PD, et al. J Nat Cancer Inst. 2008;100(16):1167-1178.
Induction of Dendritic Cell Functions of
Macrophages and Adoptive Immune Response
Increase in alfa/beta T cells activities (Adoptive responses)
Increase in gamma/delta T cells activieties (Innate responses)
GAPDH
347-
Fiore F, et al. Blood. 2007;110(3):921-927.
11
Bisphosphonate Triangle
via Ras protein inhibitions
Apoptosis
Leukemia1
RCC2
Lung cancer3
Osteosarcoma4
Bladder cancer5
BP
 T cell
Osteoclast
RCC, renal cell carcinoma; BP, bisphosphonate; , gamma-delta.
1. Kuroda J, et al. Blood. 2003;102(6):2229-2235; 2. Yuasa T, et al. Clin Cancer Res. 2005;11(2 Pt 1):853-859;
3. Matsumoto S, et al. Lung Cancer. 2005;47(1):31-39; 4. Horie N, et al. Br J Cancer. 2007;96(2):255-261;
5. Sato K, et al. Br J Cancer. 2006;95(10):1354-1361.
Gamma-delta (V9/v2) T cells:
• ~1-5% of PBMC in healthy human adults
• First line defense against pathogens
(non-peptidic compounds like phosphoantigens)
• Spontaneous antitumor activity in vitro
(MM and NHL cell lines)
• Involved in immunosurveillance in vivo
(2M-/-; PF-/- mice)
• Enhancers of adaptive immune responses
(DC, antibody production)
• Activated and expanded by nBPs
(Kunzman et al, N Engl J Med.
1999;340(9):737-738)
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Does Zoledronic Acid Induce a Tumor Antigen?
HMG-CoA
Mevalonate
Increased IPP in
cells may become
tumor antigen.
Isopentenyl-PP
Geranyl-PP
Zoledronic acid
Squalene
Cholesterol
 T cell
FPP synthase
Farnesyl-PP
Farnesylation
(panRas,Rheb etc.)
Geranylgeranyl-PP
Geranylgeranylation
Reprinted from Sato K, et al. Int J cancer. 2005;116(1):94-99.
Cancer cells
(K-Ras, N-Ras, RhoA, etc.)
Zoledronic Acid Increases Activity of
 T Cells and Other Immune Pathways
2. IPP stimulates
, T cells to proliferate and
secrete cytokines
1. ZOL inhibits FPPS
in PBMCs, causing
accumulation of IPP
ZOL
ZOL
ZOL
X
FPPS
IPP
IPP
IPP
ZOL
IL-4
IL-10
3. Activated , T cells
are directly cytotoxic
to tumor cells
4. IL-4, IL-10 stimulate
B cell humoral response
to tumor cells
Santini D, et al. Cancer Immuno Immunother. 2009 Jan;58(1):31-38.
TNF-
IFN-
5. TNF-, IFN- stimulate
antigen-presenting cells
and T-helper cells
15
 T Cells Attack Myeloma Cells
 T Cell After 2 Weeks of Ex Vivo Expansion
9.4%
 T cell = 4.6%
IL-2
86%
PB (Pre)
IL-2
+
ZOL
IL, interleukin; PB, peripheral blood; PRE, pretreatment; ZOL, zoledronic acid.
Reprinted from Sato K, et al. Int J Cancer. 2005;116(1):94-99.
Osteoblasts
Cancer stem cell niche
Low doses of ZOL increased
OPG protein secretion and
reduced transmembrane
RANKL protein expression
in osteoblast-like cells
Osteoclast activity
Bone turnover
Pan B, et al. J Bone Miner Res. 2004 Jan;19(1):147-54.
18
Bone Marrow Stromal Cells (BMSCs)
Cancer stem cell niche
Tumor cells localize within the BM through the interaction of adhesion
receptors with their ligands on BM stromal cells (BMSCs)
BMSCc from MM patient
ZOL 50
microg
Increase in apoptosis
Decrease of adhesion molecules, CD106, CD54, CD49d, and CD40
Decrease in proliferation
Corso A, et al. Cancer. 104(1):118-125.
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Circulating Endothelial Cells (CEC)
Circulating endothelial Progenitors (CEP)
Cancer stem cell niche
CEC and CEP from human PBMC
Inhibition of endothelial
progenitor cell
differentiation at low doses
(1-10 mM)
Induction of endothelial
progenitor cell apoptosis at
higher doses (> 10 mM)
Yamada J, et al. J Surg Res. 2009;151(1):115-120.
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Mesenchimal Staminal Cells (MSCs)
Cancer stem cell niche
Bone marrow MSCs increase breast cancer motility and invasion by secreting RANTES
Zoledronic acid inhibits RANTES
secretion by MSCsa
Zoledronic acid inhibits migration
of MSCsa
a
Images not available.
Normanno N, et al. Presented at ECCO 2009. Abstract 35LBA.
21
Cancer Staminal Cells (CSCs)
Cancer stem cell niche
Colon cancer comprises a small population of cancer stem cells (CSC) that
is responsible for tumor maintenance and resistant to cancer therapies
Zoledronic acid sensitizes colon CSCs to  T cell-mediated killing
P#2
P#4
P#6
P#8
P#9
HD#1
HD#2
HD#3
Cytotoxicity (%)
100
50
CSC#1
CSC#2
CSC#3
CSC#4
Todaro M, et al. J Immunology. 2009;182:7287-7296.
CSC#5
CSC#6
CSC#7
CSC#8
Zol
Nil
Zol
Nil
Zol
Nil
Zol
Nil
Zol
Nil
Zol
Zol
Nil
Nil
Zol
Nil
Zol
Nil
0
CSC#9
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Conclusions
Cancer stem cell niche
 Disseminated tumor cells (DTCs)1
yes (apoptosis)
 Osteoclast2 and macrophages3
yes (apoptosis, APC functions)
 Osteoblasts4
yes (decrease RANKL, increase OPG)
 Bone Marrow Stromal cells5
yes (< prolif; > apoptosis)
(apoptosis, inhibit. differentiation)
Prevention ofyes metastases
 CEP and CEC6
 Gamma/delta7 and alfa/beta T8
yes (immunomodulation)
 MSC (Mesenchimal Stem Cells)9
yes (inhibition of migration and cytokine secretion)
 Cancer Stem Cells10
yes (sensitizes colon CSCs to g/d T cell cytotoxicity)
• HSC VEGFR1 or 2 pos
?
Reduction of DTCs, inhibition of bone turnover, inhibition
of angiogenesis, inhibition of growth factors, stimulation
of antitumoral innate and adoptive immunity, inhibition of MSC,
inhibition of CSCs
1. Lin A, et al. ASCO. 2008; Abstract 559; 2. Dunford Je, et al. J Pharmacol Exp Ther, 2001; 3. Tsagozis P et al. Cancer
Immunology and Immunotherapy, 2008; 4. Pan B. et al. J Bone Miner Res, 2004; 5. Corso A. et al. Cancer 2005; 6.
Yamada J et al. J Surg Res, 2009; 7. Kunzmann V et al. Blood 2000; 8. Fiore F et al. Blood 2007: 9. Normanno N. et al
ECCO-ESMO, 2009; 10. Dieli F. et al. Journal of Immunology, 2009
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Combination Therapy in Vivo
Tumour type
BP
Effect
Cytotoxic drug
Breast cancer
(MDA-MB-231 IT)
Prostate cancer
Risedronate
150ug/kg/5x/week
Docetaxel
4mg/kg/2x/week
 Tumour size
Zoledronic acid
1ug/kg/day
IM (1mg/d)
Pac (0.16mg/week)
 Lymph node mets
 Tumour incidence
(van Beek 2009)
(Kim, 2005)
Ewing Sarcoma
Prostate cancer (PC3)
Osteosarcoma
Leukemia (BV173)
 Tumour incidence
Zoledronic acid
4ug/2x/week
Paclitaxel (12mg/week)
Zoledronic acid
8ug/2x/week
SC-236 (0.24mg 5x/w)
Gefitinib (3mg 5x/w)
 Tumour growth
Zoledronic acid
4ug/week
IFO 0.3mg 3x
 Tumour recurrence
Zoledronic acid
1.6ug/kg/3x/week
IM (2.4m/d)
(Zhou, 2005)
(Melisi ,2005)
(Heymann, 2005)
 Overall survival
(Kuroda, 2003)
In all cases - combination therapy superior to single
agents
Reprinted from Brown HK and Holen I. Curr Cancer Drug Targets. 2009;9(7):807-823.
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Ongoing Studies
25
ZEUS: Zoledronic Acid for the Prevention
of Bone Metastases in Prostate Cancer
Key endpoints: Time to bone metastases, overall survival,
PSA doubling time, substudies on bone markers, adverse
events
1,433 patients
Prostate cancer, M0
+/- previous local curative
treatment, +/- ADT
High-risk PCa with at least 1 of
the following criteria
• Gleason Score 8 - 10
• pN+
• PSA  20 at diagnosis
Zoledronic acid 4 mg q 3 months
R
No zoledronic acid
Treatment duration 4 years
Accrual complete
ADT, androgen deprivation therapy; PC, prostate cancer; PSA, prostate-specific antigen.
26
RADAR: Zoledronic Acid for the Prevention of Bone
Metastases and Effects on Overall Survival in PC
•
Key endpoints: PSA relapse-free survival, overall survival, local failure,
QOL, bone metastases-free survival, bone mineral density
Short-term AD (STAD) – LHRH analogue for 5
mo before and during first mo of radiation
treatment (total 6 mo)
1,071 patients
Prostate Cancer
T2a (Gleason score >/= 7 and
PSA >/= 10), T2b-4, N0, M0
Stratification
• T2a/T2b/T3,4
• <60 yr/60 - 70 yr/>70 yr
• Gleason primary pattern 1 - 3/4, 5
• PSA <10/10 - 20/>20
• Treatment center
R
Participating Countries: Australia, New Zealand
ClinicalTrials.gov identifier: NCT00193856
Short-term AD (STAD) – LHRH analogue for 5
mo before and during first mo of radiation
treatment (total 6 mo)
+ ZOL 4 mg q 3 mo / 18 mo
Intermediate term AD – LHRH analogue as for
STAD arm, but continued for further 12 mo
(total 18 mo)
Intermediate term AD – LHRH analogue as for
STAD arm, but continued for 12 mo (total 18
mo)
+ ZOL 4 mg q 3 mo / 18 mo
ZOL treatment 18 mo
total follow-up 5 years +
27
STAMPEDE: Zoledronic Acid for the Effects on
Failure-Free Survival in Prostate Cancer
•
Key endpoints: Failure-free survival (PSA failure, new lesions or increase
of baseline lesions, death), QOL, cost-effectiveness, toxicity, SREs,
overall survival
Androgen suppression (AD)
patientsa
1,264
Prostate Cancer
High-risk newly diagnosed
or relapsed after
prostatectomy or
radiotherapy who start ADT
therapy (patients with or
without bone metastases)
AD + Taxotere (T)
R
AD + zoledronic acid (Z)
AD + celecoxib
AD + celecoxib + Z
Pilot
Confir
m
Safety
in 210
patient
s on
trial for
min 18
weeks
AD + T + Z
24 months ZOL
•
Efficacy
stages I IV
Reject
arms not
improving
FailureFree
Survival at
each stage
Follow-up until death
• Participating Countries: United Kingdom
a
Enrollment current as of October 2009. Planned enrollment is between 2,800 and 3,600 patients.
28
Conclusions
• Substantial evidence from a range of models show
that BPs reduce tumour growth in bone
• Increasing evidence that BPs may also affect
tumours outside the skeleton (but the dosing/
scheduling often intensive)
• BPs may have a substantial anti-tumour effect when
used in combination with other anti-cancer agents
29