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Gentile Alessandra Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità C
1. Progressione tumorale: nuovi target
terapeutici
Alessandra Gentile
Institute for Cancer Research and Treatment - IRCC,
University of Turin School of Medicine
3. About Invasive Growth
• Invasive growth is a physiological process that
occurs during embryonic development and post-
natal tissue regeneration.
• The genetic program includes control of
proliferation, cell-scattering, migration and
protection from apoptosis.
• The MET oncogene, encoding the HGF receptor,
is a key regulator of invasive growth
4. About Invasive Growth
• Invasive growth is a physiological process that
occurs during embryonic development and post-
natal tissue regeneration.
• The genetic program includes control of
proliferation, cell-scattering, migration and
protection from apoptosis.
• The MET oncogene, encoding the HGF receptor,
is a key regulator of invasive growth
5. About Invasive Growth
• Invasive growth is a physiological process that
occurs during embryonic development and post-
natal tissue regeneration.
• The genetic program includes control of
proliferation, cell-scattering, migration and
protection from apoptosis.
• The MET oncogene, encoding the HGF receptor,
is a key regulator of invasive growth.
6. The MET oncogene, encodes the HGF receptor
HGF (Scatter Factor) Sema domain
500 AA
MRS
G-P rich (PSI)
Ig like domains
400 AA
Kringles Protease-
like
Tyrosine Kinase P
P
P
P
Met
(HGF Receptor)
7. Invasive growth is controlled by specific factors
EGF
MLP-29 (Liver stem/progenitor cells)
8. Invasive growth is controlled by specific factors
HGF
MLP-29 (Liver stem/progenitor cells)
9. HGF
Met Receptor
(tyrosine kinase)
Signal transduction
Expression of
a selective set of Genes
(The Met Signature)
Invasion & Growth
10. Plexin B1
MET
Integrin α6β 4
CD44v6
Link to cytoskeleton P
P
PI3K PI3K
p85 P p85
CRKL
P GAB1
RAS GRB2 PLCγ
GRB2P
STAT SHP2
P
Transient MAP kinase SRC
activation (proliferation)
Cell-Polarity and
Morphogenesis
Sustained MAP and PI3 kinase
activation (invasion / apoptosis
C.Boccaccio and P.M.Comoglio. Nature Rev. Cancer.
protection)
2006, 6: 637-645.
11. HGF
Met Receptor
(tyrosine kinase)
Signal transduction
Expression of
a selective set of Genes
(The Met Signature)
Invasion & Growth
12. About MET
• The MET oncogene, controls the selective
expression of a functional cluster of genes (The
“Invasive Growth Signature”)
• The “Signature” can be exploited for the prognosis
of some invasive-metastatic cancers
13. MET regulated genes
( The Invasive Growth Signature )
HGF (hours) Immediate Delayed
Early Early Late
1 6 24
Delayed
Early
Biphasic
Immediate
Early 2x induced
Tonic
Biphasic
Tonic
Late
Total = 250
genes 2x suppressed
14. 5
years
The “metagene”
Avg.Cluster A
- Avg. Cluster B
Cluster
A
Cluster
B
Tumor samples, ordered by survival time
2x induced
2x suppressed
E.Medico et al.(unpublished)
15. About the MET gene
and Cancer
• It is over-expressed in response to unfavourable
micro-environmental conditions, such as hypoxia :
“Oncogene Expedience”.
• It is constitutively activated in some cancers, by
amplification, mutations or autocrine loops:
“Oncogene Addiction”.
• It is good candidate for targeted therapies
16. Hypoxia promotes invasive growth
by transcriptional activation of the MET Oncogene
Cellular [O2]
Proteasome
degradation HIF Proline Hydroxylase
pVHL HIF-1α
α -OH α (regulated)
Cytoplasm
Nucleus
HIF-1αβ
HIF-1β
β
(constitutive)
P (-2619) S (-411) S (-345) A (-253) A (-32) START S (+89) A (+353)
AP-1
HRE-1 HRE-2 asHRE-1 asHRE-2/ HRE-4 HRE-5
S (-295) HRE-3
The MET promoter
Pennacchietti et al. , Cancer Cell 3: 347 (2003)
17. About the MET gene
and Cancer
• It is over-expressed in response to unfavourable
micro-environmental conditions, such as hypoxia
or ionizing radiations: “Oncogene Expedience”.
• It is constitutively activated in some cancers, by
amplification, mutations or autocrine loops:
“Oncogene Addiction”.
• It is good candidate for targeted therapies
18. MET oncogene mutations in Human Ca.
Sema
PSI
IPT
S985
Juxtamembrane P
Y1003
domain P
ATP-binding
region
P Y1234
KD Activation 1235
Loop PY
C-terminal
loop
P Y1349
Docking site Y1356
P
G.Stella, S.Benvenuti et al, submitted
19. MET oncogene amplification in Human Ca.
C GTL16
MET gene amplification
C GTL16
MET Protein overexpression
20. About the MET gene
and Cancer
• The oncogene encodes a tyrosine-kinase receptor
for HGF (“Scatter factor”)
• It is over-expressed in response to unfavourable micro-
environmental conditions, such as hypoxia or ionizing
radiations: “Oncogene Expedience”.
• It is constitutively activated in some cancers, by
amplification, mutations or autocrine loops:
“Oncogene Addiction”.
• It is good candidate for targeted therapies
21. Therapeutic inactivation of the MET oncogene
can be achieved by:
1. Small molecules inhibiting the Tyrosine Kinase
2. Monoclonal Antibodies inducing Met
“Shedding”
22. In vitro therapy of Met–addicted human gastric Ca
to a specific kinase inhibitor (small molecule)
A. Bertotti, L.Trusolino et al., Science Signaling, 2, issue 100, Dec. 2009
23. MET Dependency correlates
with gene amplification
<3% MET
Cell Line
ADDICTION copy N°
EBC-1 5.8
MKN-45 6
GTL-16 6.1
97 % HS746T 6.3
EXPEDIENCE
P.M.Comoglio and L.Trusolino, Nature Rev. Cancer, In preparation
24. Gene Therapy with MET antibody
Gene transfer of Lentiviral vector carrying the cDNA for DN30
into the tumor: Cancer cells produce the Monoclonal Antibody
25. Gene transfer of DN30 RF anti-Met antibodies
Inhibits growth of U87-MG Glioblastoma
xenotransplants
.
100
90
% tumor-free animals
80
70
free
60
50
40
DN30 RF MAb cDNA
30
20 ctrl
10
0
2 6 10 14 18 22 26 30 34 38 42 46 50 54 58
Time (days)
E.Vigna et al.,Cancer Res. 2008;68:9176
26. What next ?
• Oa-5d5 antibody, Genetech, preclinical
• DN30 antibody, Metheresis, preclinical
• PF2341066, small molecule, Pfizer, phase I/II clinical
• XL880, small molecule, Exelesis, phase I clinical
• ARQ197, small molecule, ArQule, phase I/II clinical
• MK2461, small molecule, Merck, phase I/II clinical
• SGX523, small molecule, SGX pharma., Phase I clinical
• JNJ38877605, small molecule, J&J, preclinical
From P. Comoglio et al, Nature Rev. Drug Discovery, 7, 504
29. Orphan Receptor protein expression
in cancer cell lines
Screened cancer cells
85
98%
human cancer cell panel
2 phospho-Ror1 positive cells
2%
NCI-H1993
HS746T
33. IRCC – Candiolo (Italy)
Director: Paolo M. Comoglio MD
Met and miRNA Met & Hypoxia Met gene therapy
S. Giordano P.Michieli E.Vigna
S. Corso S.Pennacchietti G.Pacchiana
A. Petrelli M.Galluzzo R.Albano
C. Migliore C.Basilico
Met- signature Met & Stem cells Met Addiction
E.Medico C.Boccaccio L.Trusolino
L.Lazzari F.De Bacco A.Bertotti
P.Luraghi D.Torti
S. Gastaldi F.Galimi
Met Mutations G.Reato
S. Benvenuti Plexins
M.F. Di Renzo L.Tamagnone
A.Casazza
