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„HERCEPTIN and SUTENT (Sunitinib):
From mono-specific to
multi-targeted cancer therapies“
Axel Ullrich
Max-Planck-Institute of Biochemistry
Martinsried, Germany
Targeted Cancer Therapy
„The dream of the Magic Bullet“
Side Effect-Free Cure of Cancer
Paul Ehrlich 1854 - 1915
• Father of Chemotherapy
• Salvarsan for Treatment of Syphilis
• Nobel Prize 1908
• “Magic Bullet Concept”
Hallmarks of Cancer
Target Areas for Therapeutic Interventions
Aneuploidy
Angiogenesis
Imune Defense
Evasion
Altered Energy
Metabolism
Immortalization
(Anti-Apoptosis)
Deregulated
Proliferation
Invasivity
Motility
Signalling Pathways
Human Epidermal Growth Factor
Receptor (EGFR)
Size: 170.000 Da
Length: 1186 aa
131.000 MW
mRNA: 5.8 / 10.5 kb
Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P,
Ullrich A, Schlessinger J, and Waterfield MD (1984). Close similarity of
epidermal growth factor receptor and v-erb-B oncogene protein
sequences. Nature 307. 521-527
Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, Lee J,
Yarden Y, Libermann TA, Schlessinger J, Downward J, Bye J, Whittle N,
Waterfield MD, and Seeburg PH (1984). Human epidermal growth factor
receptor cDNA sequence and aberrant expression of the amplified gene
in A431 epidermoid carcinoma cells. Nature 309. 418-425
EGFR / v-erbB
EGF-R
v-erbB-H
v-erbB-ES4
F/S699
F/S699
I/V705
T/K718
H/R811
Q/L840
S/I932
Δ1034
Δ 1042-1062
Y/N1091
Human EGF Receptor-Related Receptor
HER2 / neu / c-erbB2
Size: 185.000 Da
Length: 1234 aa
136.000 MW
mRNA: 4.8 kb
King CR, Kraus MH, and Aaronson SA. (1985) Amplification of a Novel verbB-related Gene in a Human Mammary Carcinoma. Science 229, 974976
Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg
PH, Libermann TA, Schlessinger J, Francke U, Levinson A, and Ullrich A.
(1985) Tyrosine kinase receptor with extensive homology to EGF receptor
shares chromosomal localization with neu oncogene. Science 230, 11321139
Schechter AL, Hung MC, Vaidyanathan L, Weinberg RA, Yang-Feng TL,
Francke U, Ullrich A, and Coussens L (1985). The neu gene: An erbBhomologous gene distinct from and unlinked to the gene encoding the EGF
receptor. Science 229. 976-978
From Science to Blockbuster
“The Herceptin Story”
Genentech:
R. Hudziak
M. Shepard
B. Fendley
P. Carter
Herceptin Development Team
Collaborator:
D. Slamon, UCLA
Genentech Inc.
HERCEPTIN History
Cloning of
EGFR cDNA
Relation to
V-erbB
Slamon et al.
Science
HER2 gene
amplification
in Breast Cancer
and correlation
with disease
progression
Phase I
Rhu MAb
1984
1987
1992
1985
1989
Phase III Approval
In Europe
1995
1993
1998
2000
2002
Hudziak et al.
MAb 2C4
HER2
Phase II FDA
MCB
In
Sequence published
Approval
Anti-tumor effect
Development
Coussens et al. Of MAb 4D5 and 2C4
HERCEPTIN
•
Efficacy of Monotherapy in HER2/neu +++ Patients Low
(15%)
•
•
Reminder: Cancer is NOT a Monogenic Disease
Moving Disease Target due to Genetic Plasticity of
Tumor Cells
•
Combination Therapy
HERCEPTIN +
- Anthracyclines
- Taxotere
- Platinum Salts
- etc
From Science to Multi-Targeted
Cancer Drug
“Flk-1/VEGFR2 as Target in
Anti-Angiogenesis Therapy”
MPI for Biochemistry
Munich
MPI Biochemistry, Martinsried, Germany
Birgit Millauer
Werner Risau
SUGEN
Laura Shawver
Jerry McMahon
Annie Fong
Development Team
Collaborators
Alex Levitzki, Hebrew University, Jerusalem
Gyorgy Keri, Vichem, Budapest
Pharmacia Drug Development Team
Pfizer Clinical Development Team
SUGEN
San Francisco
RTK Subclasses
EGFR
HER2/
neu
HER2
HER4
I-R
PDGFRα VEGFR1 FGFR-1 CCK4 TRKA MET EPHA1- AXL TIE RYK DDR-1 RET ROS LTK ROR1 MUSK
IGF-1R PDGFRβ VEGFR2 FGFR-2
TRKB RON EPHA8 MER TEK
DDR-2
ALK ROR2 MDK4
IRR
CSF-1R VEGFR3 FGFR-3
TRKC
EPHB1- TYRO3
KIT
FGFR-4
EPHB7
AATYK
FLK2/FLT3
AATYK2
AATYK3
Terman et al.
Biochem Biophys Res
Commun 1992
Quinn et al.
Proc Natl Acad Sci USA
1993
Millauer et al.
Cell 1993
Gene Therapy with
Dominant-Negative VEGF-R Retrovirus
Flk-1/VEGFR2: Validation as
Anti-Angiogenesis Drug Development Target
• Receptor for VEGF
• Specifically Expressed in Endothelial Cells
• Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE
SMALL MOLECULE INHIBITORS
Chemical Structure of SU5416 An Inhibitor of VEGF Receptor Kinase
N
H
O
N
H
SU5416 3-[2, 4-dimethylpyrrol-5-yl methylidenyl]-2indolinone
SU5 416 Response in AIDS Kaposi’s Sarcoma
Protocol 5416.003, Patient #003, R-P
Before treatment with SU5416
After treatment with SU5416
Patient 018/JZH: SU5416 Response
Facial Lesions
SU5416
• Highly Selective
• Efficacious in Mouse Models
• Anti - Metastatic
• Sub – Optimal Pharmacological Properties
• Efficacious in Phase I Kaposi-Sarcoma Trial
• Colon Cancer Trial Terminated
Biochemical Effects of SU6668
a VEGFR-2, PDGFR, & FGFR RTK Inhibitor
SU6668
SU5416
O
O
N
H
N
O
O
N
H
N
Flk-1
PDGFRb
Ki Km (ATP)
FGFR-1
Ki Km (ATP)
EGFR
Ki
Km (ATP)
SU5416
0.16
0.43
0.32
6.2
19.5
2.6
>100
SU6668
2.1
0.43
0.008
6.2
1.2
2.6
>100
IC50
Mean Ki and Km values are shown (mM)
• Both compounds exhibit competitive (with respect to ATP) inhibition
• Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
SU11248
An Oral Multi-Targeted Receptor Tyrosine
Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248
A Multitargeted Kinase Inhibitor
Receptor
Ligand
PDGFR
PDGF
Tumor Expression
Glioma, HCC, NSCLC, OvCa, CaP,
melanoma, CMML*, MDS*
VEGFR
VEGF
KIT
SCF
CRC, OvCa, RCC, Melanoma, NSCLC,
Sarcomas, Breast, NET
GIST*, AML*, Melanoma, SCLC, Breast,
OvCa, Cervix, Mastocytoma*
FLT3
FLT3 Ligand
AML*, MDS*, T-ALL, Neurological
* Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse
Tumors of Patients in Phase I Clinical Trials
Baseline
Week 4
Patient with metastatic renal cell carcinoma
Phase I trials ongoing at multiple international sites
• Patients heavily pre-treated, with progressive disease at entry
• Confirmed partial responses observed
SU11248 is well tolerated
• most common toxicities seen in patients are fatigue, GI, and hematologic
toxicity
Eric Raymond et al., 2002 NCI/EORTC/AACR
SU 11248/SUTENT
August 2005:
Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of
Gleevec-Resistant GIST
January 26, 2006:
FDA approves SUTENT for treatment of Gleevecresistant GIST and RCC
July 19,2006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Before Treatment
After 4 weeks of Sunitinib
Lung lesion response in RCC;
Courtesy of Dr. Ronald Bukowski, Cleveland Clinic Foundation
Sunitinib is new first-line therapy in metastatic Clear Cell Renal
Cell Carcinoma (RCC)
Adverse side effects are tolerable
Pfizer Pressekonferenz, 19 September 2006, Steigenberger Hotel Hamburg
Sunitinib in Breast Cancer Patients
• Open multicentric phase II study with 64 patients
• Patients had been treated with chemotherapy that included at least
an anthracycline or a taxane
– In average, patients had received 3.5 different chemotherapies
– 85% of patients had received adjuvant chemotherapy
• Primary endpoint: Response (RECIST)
• Secondary endpoints: 1-year – survival, duration of response,
tolerance
Miller et al., ASCO 2005, Oral Presentation May 16
Results
• Sunitinib has significant efficacy when used as a
monotherapy in patients with breast cancer
• Partial response in 14% of patients (who had been
treated before with various chemotherapeutic agents)
• Moderate Side Effects
Miller et al., ASCO 2005, Oral Presentation May 16
From Mono- to Multi-Targeted
Kinase Inhibitors
O
O
OH
N
H
O
N
H
SU5416
N
H
O
N
H
SU6668
N
H
N
H
O
F
N
H
SU11248
N
SUTENT History
Flk-1 shown to
be VEGF-R
(Millauer et al.,
Quinn et al.)
1993
Dominant negative
VEGFR-2
Inhibits tumor
angiogenesis andgrwoth in vivo
(Millauer et al.)
1994
SU5416
inhibits tumor
growth
In vivo (Fong
et al.)
1999
SU11248 orally
active
multi-targeted drug
(O‘Farrell et al.)
2003
SUTENT
approval by FDA
and EMEA
(Pfizer)
2006
Molecular Targets in Cancer
P
BMS354825
SRC
(Bristol-MS)
P
GRB-2
Receptor Tyrosine
Kinase
Imatinib (Novartis)
P
SU11248
(Pfizer)
SHC DOK
RAS-GAP
SOS
P
Zarnestra
(JNJ)
P
P
CT2584
(CTI)
P
RAS-GTP
RAS-GDP
PI3K
AKT
P
STAT1+3
RAF-1
?
P
BAY43-9006
P
P
(Bayer)
MEK1/2
SAPK
RAD001
P (Novartis)
P
CCI779 (Wyeth)
Rapamune (Wyeth) BAD
P
MAPK
BCLXL
MYC
mTOR
BCLX
BAD
14-3-3
L
Mitochondria
14-3-3
Genentech Inc.
CMM
A*STAR
MPI for Biochemistry Biopolis
Munich
Singapore
Singapore OncoGenome Project (SOG)
• Significantly Expand Cancer Mutation Database
• Start with Cancer Kinome Analysis
• Identify New Drugable Cancer Targets
• Screening of Compound Librarys – Drug Discovery and
Optimization
Future of Individualized Cancer Therapy
Diagnosis
Traditional Pathological Criteria - Tumor Gene Expression Analysis –
Germline SNP Pattern - Tumor Markers
Multi-Targeted Kinase
Inhibitors (MTKIs)
(Gleevec, SU11248)
Target Specific
Monoclonal
Antibodies
(Herceptin)
Treatment
Hormonal therapy
Radiotherapy
Traditional
Chemotherapy
(Taxol,
Anthracyclines)