preclinical strategies for precision medicine in colorectal...
TRANSCRIPT
Livio Trusolino, MD PhD
Department of Oncology, University of Turin School of Medicine
Laboratory of Translational Cancer Medicine
Candiolo Cancer Institute IRCCS
Candiolo, Turin - Italy
WIN Symposium, Paris, June 28th, 2016
Preclinical strategies for precision medicine in colorectal cancer:
Challenges and opportunities
• Receives research grants from Merus N.V., Utrecht, The Netherlands
Disclosures
• Only 10% of NSCLCs harbour EGFR mutations (in Caucasian patients), and only 40% of EGFR-mutant tumours respond to EGFR inhibitors: • overall prevalence of responders: 4%
• Only 4% of NSCLCs harbour ALK translocations, and only 50% of ALK-translocated tumours respond to ALK inhibitors:• overall prevalence of responders: 2%
• Only 10% of NSCLCs harbour EGFR mutations (in Caucasian patients), and only 40% of EGFR-mutant tumours respond to EGFR inhibitors: • overall prevalence of responders: 4%
• Only 4% of NSCLCs harbour ALK translocations, and only 50% of ALK-translocated tumours respond to ALK inhibitors:• overall prevalence of responders: 2%
Precision cancer medicine stands on exceptions
• Response to BRAF or MEK inhibition in BRAF mutant melanoma: 60%
• Response to BRAF or MEK inhibition in BRAF mutant CRC: 2%
• Response to BRAF or MEK inhibition in BRAF mutant melanoma: 60%
• Response to BRAF or MEK inhibition in BRAF mutant CRC: 2%
‘Drivers’ not always are ‘targets’
Molecular detail
Pop
ula
tio
n s
ize
TCGACGPICGC
CLI
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AL
TRIA
LS
PRECLINICAL STUDIES IN CELL LINES
ASSOCIATION STUDIES
DESCRIPTIVE STUDIES
MECHANISTIC STUDIES
Molecular detail
Pop
ula
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ize
TCGACGPICGC
CLI
NIC
AL
TRIA
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PRECLINICAL STUDIES IN CELL LINES
ASSOCIATION STUDIES
DESCRIPTIVE STUDIES
MECHANISTIC STUDIES
• In unselected patients, objective response rates to anti-EGFR antibodies are approximately 10%
• The only routine response biomarker is a negative predictor: KRAS mutations in codons 12 and 13 (40% of all CRCs)
• Other negative response biomarkers have been identified and are now progressively being introduced into diagnostic practice (rare KRAS mutations, NRAS and BRAF mutations, for an additional 15%)
• Novel response biomarkers need to be identified, together with ‘pertinent positives’ and ‘pertinent negatives’
Targeted therapies in metastatic colorectal cancer (mCRC):Limitations and open issues for precision cancer medicine
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Response to cetuximab in unselected xenopatients
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9
3 Weeks
“Quadruple negative” CRCs: Terra incognitaQuadruple WT
MET amplification
HER2 amplification
35% 22%43%
Regression: Discovery of pertinent positives
IRS2 amplification/mutation (8)
Bertotti al., Nature 2015
Regression: Discovery of pertinent positives
IRS2 amplification/mutation (8)
2
1
-1
-2
-3
0
IRS2
gen
e ex
pre
ssio
n(m
edia
n-c
ente
red
L2
R)
OR SD PD
***
Regression: Discovery of pertinent positives
IRS2 silencing lessens dependency on the EGFR pathwayQuadruple WT
MET amplification
HER2 amplification
EGF (ng/ml)
P-ERK
ERK
P-AKT
AKT
IRS2
Tubulin
Control shRNA IRS2 shRNA
0
0.2
0.4
0.6
0.8
1
1.2
Rel
ativ
e ce
ll n
um
ber
(t
reat
ed/u
ntr
eate
d)
Cetuximab (μg/ml)
Control shRNA IRS2 shRNA
Barbara Lupo
Tumour stabilisation: Discovery of co-extinction targets
Zanella et al., Science Transl. Med. 2015
IGF2 is overexpressed in a fraction of CRCs
IGF2 overexpression is enriched in mCRC cases that respond to cetuximab with disease stabilisation
-2 +2
Log2R
XenopatientsOR PDSD
Francesco Galimi
IGF2 overexpression is enriched in mCRC cases that respond to cetuximab with disease stabilisation
-2 +2
Log2R
XenopatientsOR PDSD
Khambata-Ford et al., J. Clin. Oncol., 2007 Sabine Tejpar and Eva Budinská
Patients
IGF2 targeting is synergistic with cetuximab in IGF2 overexpressors
VEH
CET
BMS
COMBO2
M040
-20 -10 10 30 50
treatment3000
2500
1500
500
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1000
0
tum
or
volu
me
(mm
3 )
400 20tu
mo
r vo
lum
e (m
m3 )
treatment2500
1500
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2000
1000
0
M053
-20 -10 10 300 20
VEH
CET
BMS
COMBO2
tum
or
volu
me
(mm
3)
tum
or
volu
me
(mm
3)
days from treatment startdays from treatment start
treatmentM053treatmentM040
low IGF2high IGF2
Francesca Cottino, Eugenia Zanella, Francesco Sassi, Giorgia Migliardi
Resistance: Discovery of actionable biomarkers
Quadruple WT
MET amplification
HER2 amplification
Resistance: Discovery of actionable biomarkers
Bertotti et al., Cancer Discovery 2011
HER2 amplification (5)
IRS2 amplification/mutation (8)
Quadruple WT
MET amplification
HER2 amplification
Resistance: Discovery of actionable biomarkers
Bardelli et al., Cancer Discovery 2013
HER2 amplification (5)
IRS2 amplification/mutation (8)
MET amplification (3)
Quadruple WT
MET amplification
HER2 amplification
Resistance: Discovery of actionable biomarkers
HER2 L866M mutation (1)
HER2 V777L mutation (2)
HER2 amplification (5)
IRS2 amplification/mutation (8)
MET amplification (3)
HER2 S310Y mutation (1)
Kavuri et al., Cancer Discovery 2015
Quadruple WT
MET amplification
HER2 amplification
Resistance: Discovery of actionable biomarkers
EGFR G465R mutation (1)
EGFR G465E mutation (1)
EGFR V843I mutation (1)
HER2 L866M mutation (1)
HER2 V777L mutation (2)
HER2 amplification (5)
IRS2 amplification/mutation (8)
MET amplification (3)
HER2 S310Y mutation (1)
Bertotti et al., Nature 2015
Resistance: Discovery of actionable biomarkers
FGFR1 amplification (3)
EGFR G465R mutation (1)
EGFR G465E mutation (1)
EGFR V843I mutation (1)
HER2 L866M mutation (1)
HER2 V777L mutation (2)
HER2 amplification (5)
IRS2 amplification/mutation (8)
MET amplification (3)
HER2 S310Y mutation (1)
Bertotti et al., Nature 2015
Quadruple WT
MET amplification
HER2 amplification
Resistance: Discovery of actionable biomarkers
PDGFRA mutation (3)
FGFR1 amplification (3)
EGFR G465R mutation (1)
EGFR G465E mutation (1)
EGFR V843I mutation (1)
HER2 L866M mutation (1)
HER2 V777L mutation (2)
HER2 amplification (5)
IRS2 amplification/mutation (8)
MET amplification (3)
HER2 S310Y mutation (1)
Bertotti et al., Nature 2015
Quadruple WT
MET amplification
HER2 amplification
Resistance: Discovery of actionable biomarkers
PDGFRA mutation (3)
FGFR1 amplification (3)
EGFR G465R mutation (1)
EGFR G465E mutation (1)
EGFR V843I mutation (1)
HER2 L866M mutation (1)
HER2 V777L mutation (2)
HER2 amplification (5)
IRS2 amplification/mutation (8)
MET amplification (3)
HER2 S310Y mutation (1)
MEK1 K57N mutation (1)
Bertotti et al., Nature 2015
Resistance biomarkers: From correlations to causative significance
Barbara Lupo
Quadruple WT
MET amplification
HER2 amplification
P-EGFR
P-ERK
Tubulin
EGFR
ERK
P-ERK
Tubulin
DDK
ERK
Mock MEK K57N
Cetuximab
(ug/ml)
Mock EGFR G465E
Cetuximab
(mg/ml)
0
0.2
0.4
0.6
0.8
1
1.2
Rela
tive c
ell
num
ber
(tre
ate
d/u
ntr
eate
d)
Cetuximab (μg/ml)
Mock MEK1 K57N
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6R
ela
tive c
ell
num
ber
(tre
ate
d/u
ntr
eate
d)
Cetuximab (μg/ml)
Mock EGFR G465E
From a black box… (2010)Quadruple WT
MET amplification
HER2 amplification
… To a rainbow of opportunities (2015)Quadruple WT
MET amplification
HER2 amplification
PDGFRA mutation (3)
FGFR1 amplification (3)
EGFR G465R mutation (1)
EGFR G465E mutation (1)
EGFR V843I mutation (1)
HER2 L866M mutation (1)
HER2 V777L mutation (2)
HER2 amplification (5)
IRS2 amplification/mutation (8)
MET amplification (3)
HER2 S310Y mutation (1)
MEK1 K57N mutation (1)
Quadruple WT
MET amplification
HER2 amplification
Therapeutic opportunities:Targeting new EGFR epitopes in EGFR-extra mutant cases
0.0
500.0
1000.0
1500.0
2000.0
2500.0
-20 -10 0 10 20 30 40
Placebo
Cetuximab
Afatinib
Cetuximab+Afatinib
Panitumumab
Panitumumab+Afatinib
Sym - PanHER
Francesco Sassi
Pan-HER
Placebo
P-ERK
days from implantation
volu
me
(mm
3)
Giorgia Migliardi, Francesca Cottino, Valentina Vurchio
0
400
800
1200
1600
2000
0 10 20 30 40 50 60 70
VEH
TRASTUZ+PERTUZ
LAPATINIB+TRASTUZ
LAPATINIB+PERTUZ
LAPATINIB
Treatment Start
days from implantation
volu
me
(mm
3)
A small molecule-antibody combination of anti-EGFR/HER2 therapies induces tumour shrinkage
CRC080
Leto et al., Clin. Cancer Res. 2015
The HERACLES trial: Targeting HER2 in KRAS WT, cetuximab-resistant mCRC
Heracles and the Hydra (Early Hellenistic Period), Musei Capitolini, Rome
Sartore-Bianchi, Trusolino et al., Lancet Oncology 2016
The HERACLES Trial: From xenopatients to patients
Andrea Bertotti
Irene Catalano
Francesca Cottino
Francesco Galimi
Simonetta M. Leto
Barbara Lupo
Acknowledgments
Giorgia Migliardi
Marika Pinnelli
Francesco Sassi
Valentina Vurchio
Eugenia R. Zanella
Alessandro Fiori
Alberto Grand
Federica Marra
Emanuele Geda
Acknowledgments
Transcriptional profiling
Claudio Isella (Candiolo)
Enzo Medico (Candiolo)
Eva Budinská (RECAMO, Brno)
Mutational profiling
Alberto Bardelli (Candiolo)
Victor Velculescu (JHU, Baltimore)
Eniko Papp (JHU; Baltimore)
Ron Bose (WUSTL, Saint Louis)
Surgery
Paolo Massucco (Candiolo)
Andrea Muratore (Candiolo)
Nadia Russolillo (Mauriziano, Torino)
Dario Ribero (IEO, Milano)
Mauro Salizzoni (Molinette, Torino)
Gianluca Paraluppi (Molinette, Torino)
Pathology
Anna Sapino (Candiolo)
Emanuele Valtorta (Niguarda, Milano)
Marcello Gambacorta (Niguarda, Milano)
Oncology
Silvia Marsoni (Candiolo)
Andrea Sartore-Bianchi (Niguarda, Milano)
Salvatore Siena (Niguarda, Milano)
Sabine Tejpar (University Hospital, Leuven)