Preclinical strategies for precision medicine in colorectal...

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

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TCGACGPICGC

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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



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IRS2 silencing lessens dependency on the EGFR pathwayQuadruple WT

MET amplification

HER2 amplification

EGF (ng/ml)

P-ERK

ERK

P-AKT

AKT

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Tubulin

Control shRNA IRS2 shRNA

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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

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Francesca Cottino, Eugenia Zanella, Francesco Sassi, Giorgia Migliardi

Resistance: Discovery of actionable biomarkers

Quadruple WT

MET amplification

HER2 amplification


Bertotti et al., Cancer Discovery 2011

HER2 amplification (5)


Quadruple WT

MET amplification

HER2 amplification


Bardelli et al., Cancer Discovery 2013



MET amplification (3)

Quadruple WT

MET amplification

HER2 amplification


HER2 L866M mutation (1)

HER2 V777L mutation (2)




HER2 S310Y mutation (1)

Kavuri et al., Cancer Discovery 2015

Quadruple WT

MET amplification

HER2 amplification


EGFR G465R mutation (1)

EGFR G465E mutation (1)

EGFR V843I mutation (1)







Bertotti et al., Nature 2015


FGFR1 amplification (3)











Quadruple WT

MET amplification

HER2 amplification


PDGFRA mutation (3)












Quadruple WT

MET amplification

HER2 amplification


PDGFRA mutation (3)











MEK1 K57N mutation (1)


Resistance biomarkers: From correlations to causative significance

Barbara Lupo

Quadruple WT

MET amplification

HER2 amplification

P-EGFR

P-ERK

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DDK

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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)











MEK1 K57N mutation (1)

Quadruple WT

MET amplification

HER2 amplification

Therapeutic opportunities:Targeting new EGFR epitopes in EGFR-extra mutant cases

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Sym - PanHER

Francesco Sassi

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Giorgia Migliardi, Francesca Cottino, Valentina Vurchio

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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)

Preclinical strategies for precision medicine in colorectal...

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