robert s. kerbel, phd canada research chair in tumor biology, angiogenesis and antiangiogenic...
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Robert S. Kerbel, PhDCanada Research Chair in Tumor Biology,Angiogenesis and Antiangiogenic Therapy
Sunnybrook Health Sciences CentreUniversity of Toronto
Acquired (“Evasive”) Resistance toAntiangiogenic Drugs and Tumor Flare-Up
2nd Quebec Conference onTherapeutic Resistance in Cancer
Montreal, November 5, 2010
Potential Conflict of Interest
• Dr. Robert S. Kerbel– Consultant (2004-present)
• Adnexus• SAB member• GSK• MolMed• Oxigene• Taiho Pharmaceuticals Japan• YM Biosciences
Bioessays 13: 31-36, 1991
Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents
Kerbel RS
Nature 390: 404-407, 1997
Antiangiogenic therapy of experimental cancer Does not induce acquired drug resistanceBoehm T, Folkman J, Browder T, O'Reilly MS
Nature 390: 335-336, 1997
A cancer therapy resistant to resistance Kerbel RS
?
Recent Clinical Trial Results Raising ConcernsAbout Antiangiogenic Therapy
1. Many phase III trials with disappointing results
failure of oral TKIsalone or when combined
with chemotherapy
failure or small PFS benefit onlywhen bevacizumab combined
with chemotherapy;no OS benefit
breast ovarian gastric prostate
and failure of 1st adjuvant phase III trials
breast prostate colon
‘CO8’ in CRC ‘AVANT’ in CRC
Llovet JM et al., N Engl J Med 359: 378-390, 2008
Sorafenib in advanced hepatocellular carcinoma
Yu et al (RS Kerbel) Science 295: 1526-1528, 2002
Effect of p53 status on tumor response to antiangiogenic therapy
Conclusions:
1.Antiangiogenic therapy selectively enriches for p53 mutant cells resistance
2. p53 mutant cells reside in more hypoxic regions distal to blood vessels
Some Proposed Modes of Acquired Resistance toVEGF Pathway–Targeting Antiangiogenic Drugs
Selection of variantshaving enhancedability to surviveunder hypoxic
conditions
Target one pathway(eg, VEGF) and acompensatory,
alternate pathwaytakes over (eg, bFGF,
IL-8, ……)
“Evasive resistance”
Rapid vascularremodeling
(maturation) ofremaining tumor
vasculature, or
“vascular co-option”
VEGF is a dominant player in tumor angiogenesis –but there are lots of other backups, eg,
PlGF(VEGFR-1)
Angiopoietins(Tie2)
Dll4(notch
receptors)
Sexhormones
bFGF
HGF/SF(c-met receptor)
IL-8
PDGF
SDF-1(CXCR4
receptor)
(FGFRs)
`tumormass
VEGF
VEGF
initiate and maintainanti-VEGF(R2)therapy
hypoxia
robustangiogenesisresumes
‘relapse’
A B C D E
initiateanti-bFGF(R)therapy
VEGF
VEGF bFGF
bFGF
'response' 'response'
From: Kerbel RS "Therapeutic implications of intrinsic or induced angiogenicgrowth factor redundancy in tumors revealed" Cancer Cell 8: 269-271, 2005.
Cancer Cell 8: 299-309, 2005
Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumorsCasanovas O, Hicklin DJ, Bergers G, Hanahan D.
“Anti-angiogenic therapy using brivanib….in a mouse model of pancreatic neuroendocrine cancer (PNET), results in sustained vascular blockade, without evidence for evasive/acquired resistance …”
Elizabeth Allen, Ian B. Walters, I. Celeste Rivera, and Douglas Hanahan
Tumors acquiring resistance to DC101 (a VEGFR-2 Mab) respond to VEGFR-2/bFGFR antagonist (brivanib)
Also, rapid development of resistance previously detected using DC101 not observed with brivanib TKI
Efficacy of the drug (brivanib) appears even more effective when used in the first-line treatment setting
Poster presented at the EORTC-NCI-AACR Molecular Targets meetingin Boston, 2009
D Huang et al, Cancer Res 70: 1063-1071, 2010
Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renalcell carcinoma.
antiangiogenictherapy H1F-1
tumor response;elevatedhypoxia
bFGF
Hypoxia/HIF-1–Mediated Upregulation of MultipleProangiogenic Growth Factors
HGF
SDF-1
Tang TC, et al (RS Kerbel). Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy. Neoplasia , in press, Nov. 2010
Response to Sorafenib, and Subsequent Relapse of Human HCC Tumors Transplanted Into the Liver
sorafenibibsorafenibib
Days
Therapy initiated~2 wks aftertransplantation
Implications for ‘Sequential / Salvage’ Therapy withVEGF Pathway Inhibitors to Treat Progressive Disease
sunitinib response relapse sorafenib
sorafenib response relapse sunitinib
bevacizumab response relapse sunitinib
HJ Burstein et al. (KD Miller), J Clin Oncol 26: 1810-1816, 2008Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane
Ebos et al., "Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy."Proc Nat'l Acad Sci, USA 104:17069-74, 2007
0 1 2 30
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07.5 mg/kg
15 mg/kg30 mg/kg
60 mg/kg120 mg/kg
Tx
R/O R/O R/O R/O C/P
26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67
Tx
Days
VE
GF
[p
g/m
L]
Sunitinib treatmentof normal micealso increases circulating G-CSF, SDF-1, SCFand OPN in a dose-dependent fashion
VEGF
SDF-1
SCF
sTIE-2
OPN
EPO
sVEGFR-2 IL-6
G-CSF PDGF-ABEbos et alPNAS 104: 17069-74, 2007
Circulating Bone Marrow-Derived Pro-angiogenic Cell Populations
RS Kerbel "Tumor Angiogenesis" New Engl J Med 358: 2039-2049, 2008
Possible consequences of the host-dependentmulti-cytokine ‘surge’ induced by antiangiogenic TKIs
1. contribute to tumor flare up/rebound?
2. contribute to drug resistance?
3. contribute to tumor growth/malignant progression?
Tumor Flare-up or 'Rebound' After Cessation of Antiangiogenic TKI Therapy
Acta Oncol. 48: 927-31, 2009
The reverse side of the victory: flare up of symptoms after discontinuation of sunitinib or sorafenib in renal cell cancer patients. A report of three cases.
Desar IM, Mulder SF, Stillebroer AB, van Spronsen DJ, van der Graaf WT, Mulders PF, van Herpen CM
Acta Oncol. 48: 621-624, 2009
Flare-up: an often unreported phenomenon nevertheless familiar to oncologists prescribing tyrosine kinase inhibitors.
Wolter P, Beuselinck B, Pans S, Schoffski P
Cancer Cell: Vol 15(3):220-239 March 3, 2009
Protocol for initial examination of the possibility of anti-angiogenic drug-induced acceleration of metastatic disease
e.g. daily treatment of normalmice with sunitinib for 7 days
e.g. daily treatment of normalmice with vehicle control for 7 days
inject luciferase taggedhuman breast cancer cells
1 day
evaluate metastatic burdenand survivaldays 5 –30
inject luciferase taggedhuman breast cancer cells
1 day
evaluate metastatic burdenand survivaldays 5 –30
-7 0 7 14 21 28 35 42
106
107
108
Group A
Group B
Group C
Group D60 mg/kg
120 mg/kg
Vehicle
Group E
120 mg/kg
120 mg/kg
60 mg/kg
i.v tumor implantation
(LM2-4LUC+ Cells)
Days Post-Implantation
Tu
mo
r B
urd
en
[Ph
oto
ns
/se
c]
Impact of Sunitinib Pretreatment (or Post-treatment) on Progression of Micrometastases
Day
s P
ost
Tu
mo
r Im
pla
nta
tio
n
7
14
21
30
Group A1 2 3 4 5 6 7
Group D1 2 3 4 5
Group E1 2 3 4 5
Group B1 2 3 4 5 6 7
Group C1 2 3 4 5 6 7
27
Ebos et al. Cancer Cell, 15: 232-239, 2009
-7 0 7 14 21 28 35 42
106
107
108
Group A
Group B
Group C
Group D60 mg/kg
120 mg/kg
Vehicle
Group E
120 mg/kg
120 mg/kg
60 mg/kg
i.v tumor implantation
(LM2-4LUC+ Cells)
Days Post-Implantation
Tu
mo
r B
urd
en
[Ph
oto
ns
/se
c]
0 50
10
20
30
40
50
60
70
80
90
100
110
Group AGroup BGroup CGroup DGroup E
30 40 50 60** ** *
Days Post-Implantation
Su
rviv
al
(%)
Impact on Survival Times
0 7 14 21 28 35 42 49 56 630
250
500
750
1000
1250
1500
1750
2000
Group A
Group B
Group C
60 mg/kg
Vehicle
120 mg/kg
Mammary fat pad orthotopic tumor implantation
(LM2-4LUC+ Cells)
**,***
}
Days Post-Implantation
Tu
mo
r V
olu
me
(m
m3)
Impact of Long Term Sunitinib Treatment on Established Primary Tumor Growth
Ebos et al., Cancer Cell 15: 232-239, 2009
Short-term adjuvant sunitinib treatment increases spontaneous metastasis after removal of primary human
breast cancer xenograft
0 7 14 21 28 35 42 49105
106
107
108
109
Group A
Group B120 mg/kg
Mammary fat pad orthotopic tumor implantation
(LM2-4LUC+ Cells)Primary tumor resection
Vehicle
Tumors grownunti l 400 mm3
Days Post-Resection
Tu
mo
r B
urd
en
[Ph
oto
ns
/se
c]
5
Before
30
Group A Group B
Day
s A
fter
Tum
or R
ese
ctio
nPhotons/se
c
Ebos et al., Cancer Cell 15: 232-239, 2009(survival times also decreased)
Ebos JM et al., Cancer Cell 15: 232-239, 2009
Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.
“Our results may be pertinent to the considerationof several prominent issues in cancer therapeutics including…… use of antiangiogenicdrugs in the adjuvant setting……”
0.0 0.5 1.0 1.5 2.0 2.5 3.0
0
20
40
60
80
100
DFS (years)
FOLFOX
+BEV
Phase III Adjuvant Bevacizumab+Chemo Phase III Adjuvant Bevacizumab+Chemo NASBP ‘CO8’ Trial in Stage II & III CRCNASBP ‘CO8’ Trial in Stage II & III CRC
HR
FOLFOXBEV only
“While we originally hoped the significant survival benefit of Avastin seen in metastatic disease in colorectal cancerwould be translated to the early setting, it is becoming increasingly clear that the effects of Avastin are different inthe metastatic and early disease settings for patients with coloncancer.’’ said Hal Barron, M.D., Head of GlobalProduct Development and Chief Medical Officer at Roche.
SKOV-3-13
10 days after intraperitoneal transplantation of luciferase positive SKOV-3 cells
Impact of Pazopanib and MetronomicTopotecan Chemotherapy in a Model
of Advanced Ovarian Cancer
SKOV-3-13Non-tumor SKOV-3-6 SKOV-3-11
K. Hashimoto et al, Mol Cancer Ther 9: 996-1006, 2010
days after start of treatment
% s
urv i
val
Impact of chronic daily metronomic oral topotecanchemotherapy plus pazopanib
K. Hashimoto et al.
Acknowledgments
John Ebos
Christina Lee
Georg Bjarnason
Kae Hashimoto
Jamie Christensen (Pfizer)