Transcript PowerPoint - Q-CROC

2nd Quebec Conference on
Therapeutic Resistance in Cancer
Montreal, November 5, 2010
Acquired (“Evasive”) Resistance to
Antiangiogenic Drugs and Tumor Flare-Up
Robert S. Kerbel, PhD
Canada Research Chair in Tumor Biology,
Angiogenesis and Antiangiogenic Therapy
Sunnybrook Health Sciences Centre
University of Toronto
Potential Conflict of Interest
• Dr. Robert S. Kerbel
– Consultant (2004-present)
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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 resistance
Boehm 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 Concerns
About Antiangiogenic Therapy
1. Many phase III trials with disappointing results
failure of oral TKIs
alone or when combined
with chemotherapy
breast prostate
failure or small PFS benefit only
when bevacizumab combined
with chemotherapy;
no OS benefit
colon
breast ovarian gastric
prostate
and failure of 1st adjuvant phase III trials
‘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 to
VEGF Pathway–Targeting Antiangiogenic Drugs
Selection of variants
having enhanced
ability to survive
under hypoxic
conditions
“Evasive resistance”
Target one pathway
(eg, VEGF) and a
compensatory,
alternate pathway
takes over (eg, bFGF,
IL-8, ……)
Rapid vascular
remodeling
(maturation) of
remaining tumor
vasculature,
or
“vascular co-option”
VEGF is a dominant player in tumor angiogenesis –
but there are lots of other backups, eg,
PlGF
Dll4
(VEGFR-1)
(notch
receptors)
IL-8
(Tie2)
Sex
hormones
(CXCR4
receptor)
bFGF
(FGFRs)
Angiopoietins
SDF-1
PDGF
HGF/SF
(c-met receptor)
Cancer Cell 8: 299-309, 2005
Drug resistance by evasion of antiangiogenic targeting of VEGF
signaling in late-stage pancreatic islet tumors
Casanovas O, Hicklin DJ, Bergers G, Hanahan D.
A
B
C
D
initiate
anti-bFGF(R)
therapy
initiate and maintain
anti-VEGF(R2)
therapy
VEGF
tumor
`
mass
VEGF
bFGF
robust
angiogenesis
resumes
hypoxia
VEGF
VEGF
'response'
E
bFGF
‘relapse’
'response'
From: Kerbel RS "Therapeutic implications of intrinsic or induced angiogenic
growth factor redundancy in tumors revealed" Cancer Cell 8: 269-271, 2005.
Poster presented at the EORTC-NCI-AACR Molecular Targets meeting
in Boston, 2009
“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
D Huang et al, Cancer Res 70: 1063-1071, 2010
Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal
cell carcinoma.
Hypoxia/HIF-1–Mediated Upregulation of Multiple
Proangiogenic Growth Factors
bFGF 
antiangiogenic
therapy
tumor
response;
elevated
hypoxia
H1F-1 
HGF 
SDF-1 
Response to Sorafenib, and Subsequent Relapse
of Human HCC Tumors Transplanted Into the Liver
sorafenibib
sorafenibib
Therapy initiated
~2 wks after
transplantation
Days
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
Implications for ‘Sequential / Salvage’ Therapy with
VEGF 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, 2008
Phase 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
650
Tx
Tx
600
550
VEGF [pg/mL]
500
450
400
350
0
7.5 mg/kg
15 mg/kg
30 mg/kg
60 mg/kg
120 mg/kg
300
250
200
150
100
50
0
0
1
R/O
2
3 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
R/O
R/O
R/O
Days
C/P
Sunitinib treatment
of normal mice
also increases
circulating G-CSF,
SDF-1, SCF
and OPN in a dosedependent fashion
Ebos et al
PNAS 104: 17069-74, 2007
VEGF
sTIE-2
SDF-1
OPN
SCF
EPO
sVEGFR-2
IL-6
G-CSF
PDGF-AB
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-dependent
multi-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 antiangiogenic drug-induced acceleration of metastatic disease
e.g. daily treatment of normal
mice with sunitinib for 7 days
1 day
e.g. daily treatment of normal
mice with vehicle control for 7 days
1 day
inject luciferase tagged
human breast cancer cells
inject luciferase tagged
human breast cancer cells
evaluate metastatic burden
and survival
days 5 –30
evaluate metastatic burden
and survival
days 5 –30
Impact of Sunitinib Pretreatment (or Post-treatment) on
Progression of Micrometastases
i.v tumor implantation
(LM2-4LUC+ Cells)
Vehi cl e
Group A
120 m g/kg
Group B
120 m g/kg
Group C
120 m g/kg
Group A
3
4
5
6
Group D
60 m g/kg
Group E
Group B
7
1 2
3
4
5
6
Group C
7
1 2
3
4
5
6
Group D
7
1 2
3
4
5
10 8
7
Tumor Burden
[Photons/sec]
Days Post Tumor Implantation
1 2
60 m g/kg
14 10
7
21
10 6
27
-7
30
0
7
14
21
Days Post-Implantation
Ebos et al. Cancer Cell, 15: 232-239, 2009
28
35
42
Group E
1 2
3
4
5
Impact on Survival Times
i.v tumor implantation
(LM2-4LUC+ Cells)
Vehi cl e
Group A
120 m g/kg
Group B
120 m g/kg
Group C
120 m g/kg
60 m g/kg
Group D
60 m g/kg
Group E
110
100
90
80
10 7
10 6
Survival (%)
Tumor Burden
[Photons/sec]
10 8
70
60
50
40
30
20
-7
10
0
Group
Group
Group
Group
7
Group
A
B
C
D
14
21
E Days Post-Implantation
**
0
0 5
30
40
28
**
50
Days Post-Implantation
35
42
*
60
Impact of Long Term Sunitinib Treatment on Established Primary Tumor Growth
Mammary f at pad orthotopic tumor implantation
(LM2-4LUC+ Cells)
Vehi cl e
Group A
60 m g/kg
Group B
120 m g/kg
Group C
2000
Tumor Volume (mm3)
1750
1500
1250
1000
750
500
}
250
**,***
0
0
7
14
21
28
35
42
Days Post-Implantation
Ebos et al., Cancer Cell 15: 232-239, 2009
49
56
63
Short-term adjuvant sunitinib treatment increases spontaneous
metastasis after removal of primary human breast cancer xenograft
Mammary f at pad orthotopic tumor implantation
(LM2-4LUC+ Cells)
Primary tumor resection
T um ors grown
unti l 400 m m 3
Vehi cl e
Group A
120 m g/kg
Group B
10 9
Group B
Group A
10 8
5
Tumor Burden
[Photons/sec]
Days After Tumor Resection
Before
10 7
10 6
30
10 5
0
7
14
21
28
35
42
49
Days Post-Resection
(survival times also decreased)
Ebos et al., Cancer Cell 15: 232-239, 2009
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 consideration
of several prominent issues in cancer
therapeutics including…… use of antiangiogenic
drugs in the adjuvant setting……”
Phase III Adjuvant Bevacizumab+Chemo
NASBP ‘CO8’ Trial in Stage II & III CRC
100
FOLFOX
FOLFOX
+BEV
1.00
60
80
BEV only
0.80
0.81
0.87
0.74
40
0.60
0.40
0.85
0.6
HR
20
0.20
0.00
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.5
1.0
1.5
2.0
2.5
3.0
DFS (years)
“While we originally hoped the significant survival benefit of
Avastin seen in metastatic disease in colorectal cancer
would be translated to the early setting, it is becoming
increasingly clear that the effects of Avastin are different in
the metastatic and early disease settings for patients with colon
cancer.’’ said Hal Barron, M.D., Head of Global
Product Development and Chief Medical Officer at Roche.
Impact of Pazopanib and Metronomic
Topotecan Chemotherapy in a Model
of Advanced Ovarian Cancer
10 days after intraperitoneal transplantation of luciferase positive SKOV-3 cells
SKOV-3-13
Non-tumor
SKOV-3-6
SKOV-3-11
SKOV-3-13
K. Hashimoto et al, Mol Cancer Ther 9: 996-1006, 2010
Impact of chronic daily metronomic oral topotecan
chemotherapy plus pazopanib
days after start of treatment
K. Hashimoto et al.
Acknowledgments
John Ebos
Christina Lee
Georg Bjarnason
Kae Hashimoto
Jamie Christensen (Pfizer)