Colorectal cancer xenopatients: A preclinical platform for precision medicine
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1 Colorectal cancer xenopatients: A preclinical platform for precision medicine Livio Trusolino, MD PhD Laboratory of Molecular Pharmacology IRCC, Institute for Cancer Research and Treatment University of Torino School of Medicine TAT 2013, Paris, 6th March 2013
2 Andrea Bertotti Giorgia Migliardi Francesco Sassi Francesco Galimi Francesca Cottino Eugenia Zanella Flavia Di Renzo Silvia Marsoni Paolo Comoglio Surgery Paolo Massucco (IRCC) Andrea Muratore (IRCC) Nadia Russolillo (Mauriziano) Dario Ribero (Mauriziano) Lorenzo Capussotti (Mauriziano) Gianluca Paraluppi (Molinette) Mauro Salizzoni (Molinette) Acknowledgments Transcriptional profiling and SNPChip analyses Claudio Isella Davide Corà Consalvo Petti Daniela Cantarella Barbara Martinoglio Roberta Porporato Enzo Medico Pathology Alberto Pisacane (IRCC) Mauro Risio (IRCC) Bruno Torchio (Mauriziano) Ezio David (Molinette) Luca Molinaro (Molinette) Anna Sapino (Molinette) Giorgio Inghirami (Molinette) Emanuele Valtorta (Niguarda) Marcello Gambacorta (Niguarda) Mutational profiling Federica Di Nicolantonio Michela Buscarino Alberto Bardelli Oncology Andrea Sartore Bianchi (Niguarda) Roberta Schiavo (Niguarda) Salvatore Siena (Niguarda) Francesco Leone (IRCC) Filippo Montemurro (IRCC) Massimo Aglietta (IRCC)
3 Precision cancer medicine stands on exceptions Only 10% of NSCLCs harbour EGFR mutations, and only 40% of EGFRmutant tumours respond to EGFR inhibitors: overall prevalence of responders: 4% Only 4% of NSCLCs harbour ALK translocations, and only 50% of ALKtranslocated tumours respond to ALK inhibitors: overall prevalence of responders: 2% Response to BRAF or MEK inhibition in BRAF mutant melanoma: 60% Response to BRAF or MEK inhibition in BRAF mutant CRC: 2% Trusolino and Bertotti, Cancer Discovery, 2012
4 Precision cancer medicine stands on exceptions Only 10% of NSCLCs harbour EGFR mutations, and only 40% of EGFRmutant tumours respond to EGFR inhibitors: overall prevalence of responders: 4% Only 4% of NSCLCs harbour ALK translocations, and only 50% of ALKtranslocated tumours respond to ALK inhibitors: overall prevalence of responders: 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 Exceptions become rules only if confirmed on a population basis
5 Population size CLINICAL TRIALS Current limitations of translational cancer research TCGA CGP ICGC MECHANISTIC STUDIES DESCRIPTIVE STUDIES ASSOCIATION STUDIES PRECLINICAL STUDIES IN CELL LINES Molecular detail
6 Population size CLINICAL TRIALS Overcoming limitations with xenopatients TCGA CGP ICGC MECHANISTIC STUDIES DESCRIPTIVE STUDIES ASSOCIATION STUDIES PRECLINICAL STUDIES IN CELL LINES Molecular detail
7 Aims Discovery of novel biomarkers of response and resistance to anti-egfr therapies in mcrc Validation of new biomarkers as alternative drivers of CRC tumorigenesis and progression Challenging new biomarkers as actionable therapeutic targets Genomic/molecular contextualization of novel biomarkers
8 M019 M023 M020 M025 M018 M039 M014 M004 M007 M032 M050 M021 M037 M036 M051 M030 M047 M057 M015 M042 M017 M024 M059 M035 M054 M029 M043 M048 M052 M038 M034 M040 M044 M010 M049 M012 M028 M053 M027 M005 M006 M026 M046 M031 M013 M016 M045 (% of volume) Validation of established biomarkers % % % Galimi et al., Clin. Cancer Res., 2011 Migliardi et al., Clin. Cancer Res., 2012
9 Galimi et al., Clin. Cancer Res., 2011 Migliardi et al., Clin. Cancer Res., 2012 Validation of established biomarkers
10 M122 M019 M085 M018 M039 M004 M050 M021 M066 M102 M110 M145 M071 M077 M051 M030 M121 M057 M093 M091 M015 M147 M024 M100 M137 M072 M116 M029 M052 M038 M073 M107 M040 M044 M079 M124 M068 M088 M049 M105 M065 M084 M028 M053 M117 M027 M062 M005 M098 M109 M070 M142 M006 M026 M081 M046 M064 M031 M083 M013 M016 M067 M095 M045 M078 M069 (% of volume) Validation of candidate biomarkers % % % Bertotti et al., Cancer Discovery, 2011
11 Bertotti et al., Cancer Discovery, 2011 Validation of candidate biomarkers
12 Responders vs. nonresponders in a KRAS WT (cod 12 & 13) population Mutant for KRAS codons 61 and 146, NRAS, BRAF Quadruple negative (wild-type for KRAS codons 12 and 13, KRAS codons 61 and 146, NRAS, BRAF)
13 -100% 0% 100% 200% 300% 400% 500% 600% 700% CRC0186 CRC0197 CRC0152 CRC0166 CRC0343 CRC0416 CRC0151 CRC0382 CRC0371 CRC0358 CRC0345 CRC0126 CRC0196 CRC0239 CRC0442 CRC0068 CRC0177 CRC0112 CRC0080 CRC0276 CRC0161 CRC0312 CRC0328 CRC0394 CRC0344 CRC0176 CRC0125 CRC0400 CRC0124 CRC0058 CRC0307 CRC0356 CRC0025 CRC0403 CRC0370 CRC0441 CRC0431 CRC0199 CRC0435 CRC0306 CRC0399 CRC0404 CRC0440 CRC0081 CRC0378 CRC0285 CRC0419 CRC0029 CRC0334 CRC0109 CRC0456 CRC0131 CRC0396 CRC0257 CRC0030 CRC0095 CRC0018 CRC0153 CRC0101 CRC0362 CRC0121 CRC0129 CRC0078 CRC0099 CRC0117 CRC0147 CRC0190 CRC0066 CRC0032 CRC0264 CRC0237 CRC0146 CRC0204 CRC0243 CRC0097 CRC0014 CRC0202 CRC0133 CRC0137 CRC0103 CRC0171 CRC0054 CRC0065 CRC0179 CRC0115 CRC0188 CRC0076 CRC0098 CRC0069 CRC0297 CRC0322 CRC0159 CRC0116 CRC0157 CRC0185 CRC0057 CRC0246 CRC0252 CRC0254 CRC0096 CRC0113 CRC0262 CRC0327 CRC0102 CRC Weeks Quadruple negative tumours: here be dragons Bertotti et al., Cancer Discovery, 2011
14 -100% 0% 100% 200% 300% 400% 500% 600% 700% CRC0186 CRC0197 CRC0152 CRC0166 CRC0343 CRC0416 CRC0151 CRC0382 CRC0371 CRC0358 CRC0345 CRC0126 CRC0196 CRC0239 CRC0442 CRC0068 CRC0177 CRC0112 CRC0080 CRC0276 CRC0161 CRC0312 CRC0328 CRC0394 CRC0344 CRC0176 CRC0125 CRC0400 CRC0124 CRC0058 CRC0307 CRC0356 CRC0025 CRC0403 CRC0370 CRC0441 CRC0431 CRC0199 CRC0435 CRC0306 CRC0399 CRC0404 CRC0440 CRC0081 CRC0378 CRC0285 CRC0419 CRC0029 CRC0334 CRC0109 CRC0456 CRC0131 CRC0396 CRC0257 CRC0030 CRC0095 CRC0018 CRC0153 CRC0101 CRC0362 CRC0121 CRC0129 CRC0078 CRC0099 CRC0117 CRC0147 CRC0190 CRC0066 CRC0032 CRC0264 CRC0237 CRC0146 CRC0204 CRC0243 CRC0097 CRC0014 CRC0202 CRC0133 CRC0137 CRC0103 CRC0171 CRC0054 CRC0065 CRC0179 CRC0115 CRC0188 CRC0076 CRC0098 CRC0069 CRC0297 CRC0322 CRC0159 CRC0116 CRC0157 CRC0185 CRC0057 CRC0246 CRC0252 CRC0254 CRC0096 CRC0113 CRC0262 CRC0327 CRC0102 CRC Weeks Resistance: Discovery of actionable biomarkers 35% Bertotti et al., Cancer Discovery, 2011
15 HER2 is an actionable resistance biomarker 35% Quadruple WT HER2 amplification Bertotti et al., Cancer Discovery, 2011
16 HER2 is an actionable resistance biomarker 35% Patient Xenopatient FISH HER2 CEP17 Bertotti et al., Cancer Discovery, 2011
17 Volume (mm 3 ) Only a small molecule-antibody combination of anti-her2 therapies is effective 2000 CRC Treatment Start VEH TRASTUZ+PERTUZ LAPATINIB+TRASTUZ LAPATINIB+PERTUZ LAPATINIB Days from implantation Giorgia Migliardi, Eugenia Zanella
18 The HERACLES trial: Targeting HER2 in KRAS WT, cetuximab-resistant mcrc Patient Courtesy of Salvatore Siena, Silvia Marsoni
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