FARMACI PERSONALIZZATI PER

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1 ISTITUTO NAZIONALE PER LO STUDIO E LA CURA DEI TUMORI FONDAZIONE G. Pascale NAPOLI SC Biologia Cellulare e Bioterapie CENTRO RICERCHE ONCOLOGICHE MERCOGLIANO (AV) Laboratorio di Farmacogenomica FARMACI PERSONALIZZATI PER SCONFIGGERE I TUMORI Nicola Normanno

2 IERI G1 S G2 M

3 PRE GENOME ERA

4 Signal transduction pathways involved in the proliferation and survival of cancer cells

5 POST GENOME ERA

6 Sorlie PNAS 2001

7 Tumor/Stroma interaction

8 Target based agents in clinical development in breast cancer Normanno Endocr Relat Cancer 2009

9 Sotiriou & Pusztai NEJM 2009

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11 The ErbB family of receptors and their cognate ligands EGF TGF α NRG 1 4 AR BTC HB EGF ErbB dimer BTC HB EGF EPR EPR Ligand NRG 1 2 Tomoregulin P P K K P K P K P P EGFR EbB2 ErbB 2 EbB3 ErbB 3 EbB4 ErbB 4 PI3 kinase ras AKT STAT MEK/MAPK Normanno Curr Drug Targets 2005

12 Potential sites for therapeutic intervention in growth factor driven signal transduction pathways Anti receptor or anti growth factor blocking antibodies Ct Cetuximab Panitumumab Trastuzumab EGFR, ErbB 2 Ligand or antiboby conjugated toxins Extracellular domain Cell Membrane Tyrosine Kinase Inhibitors Gefitinib Erlotinib Lapatinib Tyrosine kinase domain PI3 kinase ras Farnesyltransferase inhibitors AKT STAT MEK/MAPK Kinase inhibitors mtor Gene Transcription Nucleus Antisense oligonucleotides Normanno Endocr Relat Cancer 2003

13 Gli anticorpi monoclonali anti EGFR sono efficaci solo nei pazienti che non hanno mutazioni dell oncogene KRAS Farmaci anti EGFR nel carcinoma del colon retto Normanno Nat Rev Clin Oncol 2009

14 Mutazioni del gene EGFR nel carcinoma polmonare Gli inibitori di tirosino chinasi dell EGFR sono efficaci solo nei pazienti che presentano mutazioni dell EGFR Tyrosine kinase domain EGFR Mutations Frequency (%) Exon 19 deletions 46 L858R 40 substitution i Exon 20 variants 9 Other variants 5 De Luca & Normanno Curr Drug Targets 2010

15 IPASS Gefitinib CarboTax

16 Angiogenesis and Tumor Growth

17 DRUGS INTERFERING WITH THE VEGF PATHWAY Antibodies anti VEGFR MAb anti VEGF (bevacizumab) VEGF VEGFR 1 VEGFR 2 Soluble VEGFR (VEGF TRAP) P P P P P P P P P P P P Ribozymes (Angiozyme) Small molecules anti VEGFR (TKIs) (Sunitinib ecc.)

18 Targeted Agents in Pancreatic cancer Tipifarnib Marimastat Tanomastat (BAY ) Cetuximab Sorafenib Axitinib Lapatinib Failed Failed Failed Failed Failed Failed Failed Tarceva Approved (??!!) Bevacizumab 1. Van Cutsem E, et al. J Clin Oncol. 2004; Bramhall SR, et al. Br J Cancer. 2002;87: Moore MJ, et al. J Clin Oncol. 2003;21: Failed

19 Molecular alterations in PCa Jones Science 2008

20 Molecular alterations in PCa Jones Science 2008

21 TUMOR CELL HETEROGENEITY Tumor stem cell Autocrine Growth-loop Non-proliferative Metastatic Growth Factor Independent Non-antigenic

22 The action/reaction hypothesis ESTROGEN INDEPENDENT PHENOTYPE ACTIONS ERα degradation (Fulvestrant) Estrogen insensitive: growth factor signalling drives proliferation and survival Responder to signalling inhibitors Prolonged estrogen deprivation (AIs) Estrogen supersensitive: apparently ligand independent d activity it of ERα Responder to fulvestrant ERα-antagonists (e.g. Tamoxifen) or estrogen deprivation Estrogen hypersensitive: tumor cells adapt to respond to very low levels of estrogen Responder to AIs and fulvestrant REACTIONS ESTROGEN DEPENDENT PHENOTYPE Normanno Endocr Relat Cancer 2005

23 Mechanisms of resistance to EGFR TKIs in NSCLC B EGFR/EGFR EGFR/ErbB 3 A EGFR/EGFR EGFR/ErbB 3 T790M EGFR/EGFR MET/ErbB 3 MET TKI X X C TKI X De Luca & Normanno Curr Drug Targets 2010

24 Normanno Endocr Relat Cancer 2009

25 Next Generation Sequencing Roche/454 FLX: 2004 Platforms Illumina Solexa Genome Analyzer: 2006 Applied Biosystems SOLiD TM System: 2007 Helicos Heliscope TM : recently available Pacific Biosciencies SMRT: launching2010

26 Different sources of tumor DNA Fleischhacker & Schmidt Nat Med 2008

27 CellSearch System

28 Herbst NEJM 2008