Nuovi Scenari in Oncologia. G. Zoppoli X-Files in Nutrizione Clinica e Artificiale, 08/06/2012

Transcription

1 Nuovi Scenari in Oncologia G. Zoppoli X-Files in Nutrizione Clinica e Artificiale, 08/06/2012

2 WHAT is cancer? «Cancer is a genetic disease of the somatic cell» [B. Vogelstein]

3 Ten years ago Now [Cell Jan 7;100(1):57-70] [Cell Mar 4;144(5):646-74]

4 [Cell Mar 4;144(5):646-74]

5 We must identify alterations that characterize each individual

6 Our experience: the Translational Genomics Lab (GENOMED Consortium) The beginning: chronic myelogenous leukemia: Bcr/Abl detection (RT-PCR) The present: K-Ras in colon cancer, EGFR in lung cancer, Her2 in breast cancer (DNA-RT- PCR, acgh preliminary tests available) The future: symultaneous detection of tens of alterations in cancer (next-gen sequencing, set-up phase ongoing)

7 K-Ras activating mutations: resistance to cetuximab and panitumumab in colon cancer ERBB pathway alterations EGFR activating point mutations: sensitivity to erlotinib and gefitinib in NSCLC Her2 copy number gains: sensitivity to trastuzumab in breast cancer

8 Point mutation detection by Sanger sequencing EGFR esone 19 WT Esone 19 del E746-A752 e E746V Esone 19 K745N e E746X [Courtesy A.B. Garuti]

9 Detection of point mutations: increasing demand ; KRAS EGFR 2010; ; ; ; ; 22 0

10 Her2 amplification in breast cancer Fluorescence In Situ Hybridization (FISH)

11 Copy number alteration detection: not just FISH RT-DNA PCR: Her2/APP ratio: Suitable for small/inadequate samples Easily standardizable Extremely accurate acgh: More refined analysis look of the amplification entity May circumvent some FISH-related issues (complex karyotypes) «Brute force» analysis (several probes)

12 acgh: the principle Labeling of DNA and hybridization to DNA chip Scanning Software analysis

13 acgh: 5q- syndrome

14 Next generation sequencing (1)

15 Next generation sequencing (2) 46 genes, 739 mutations KRAS BRAF EGFR TP53 PIK3CA CSF1R JAK2 NRAS PTPN11 ERBB2 SRC FGFR3 NPM1 CDKN2A RET HNF1A SMAD4 GNAS PDGFRA MPL ABL1 PTEN FLT3 STK11 SMARCB1 KIT MET NOTCH1 FGFR2 RB1 JAK3 VHL KDR SMO HRAS AKT1 ALK MLH1 FBXW7 ERBB4 ATM CDH1 IDH1 CTNNB1 APC FGFR1 For Research Use Only. Not intended for any animal or human therapeutic or diagnostic use.

16 Next generation sequencing (3) Potential advantages of NGS in clinical practice: High throughput analysis at low costs Information concerning sensitivity/resistance to multiple drugs Identification of secondary resistance mechanisms Analysis of vaster regions of the cancer cell signaling network than previously dreamt of

17 Personalized medicine: TOMORROW The right treatment For the right person At the right moment For the right aim Our goal is to know which patients are going to respond to treatment, and if so, to which treatment

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19 The team: Medical staff: - Prof. A. Ballestrero - Prof. F. Patrone - Prof. R. Gonella - Prof. F. Ferrando - Prof. A. Nencioni - Dr. L. Tixi - Dr. R. Murialdo Molecular Biology Lab: - Prof. S. Parodi - Dr. L. Bagnasco - Dr. D. Piras Translational Biology Lab: - Dr. A. B. Garuti - Dr. I. Rocco - Dr. C. Palermo - Dr. G. Cirmena

20 Acknowledgments: AIL AIRC CARIGE Life Technologies Roche Università di Genova

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22 Because different cancers Because it s the more same type of have VERY different cancer complicated has different than alterations we alterations ever thought in each it would patient!!! Why is personalized therapy taking so long?

23 Finora, nella vasta maggioranza dei casi, si è fatto qualcosa di questo tipo: Giovanni Rossi ha la neoplasia x Iniziamo a trattarlo col farmaco y basandoci sui migliori risultati statistici possibili Aspettiamo e vediamo Modifichiamo i trattamenti finchè c è una risposta

24 Vogliamo fare qualcosa di questo tipo: Patient John Paul Shean Feature A Feature B Feature C Feature D Feature E Feature F Trattiamo il paziente con il farmaco che è efficace Feature X X X nel SUO tumore perché X conosciamo le SUE X X X Lynda alterazioni! X X

25 Per dare a LORO il farmaco giusto

26 Per dare LORO farmaci giusti alla ricaduta della malattia