Rilevanza dell'innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia ricerca traslazionale e la terapia in oncologia

Rilevanza dell'innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia ricerca traslazionale e la terapia in oncologia

Rilevanza dell’innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia ricerca traslazionale e la terapia in oncologia Ruggero De Maria Dipartimento di Ematologia Oncologia e Medicina Molecolare, Istituto Superiore di Sanità

Rilevanza dell'innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia ricerca traslazionale e la terapia in oncologia

Translational research: the central role of biotechnologies the central role of biotechnologies Bench scientists Clinical scientists Clinicians Bench scientists Clinical scientists Clinicians Pathophysiology Diseases Genomics Proteomics Clinical trials Diseases New infections Stem cells Transgenic/knockouts Structural Structural biology/Imaging Clinical problem Clinical Clinical application application

Rilevanza dell'innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia ricerca traslazionale e la terapia in oncologia

Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial py

Rilevanza dell'innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia ricerca traslazionale e la terapia in oncologia

How Could Molecular Markers Influence How Could Molecular Markers Influence Treatment Decisions? Treatment Clinical Genomic Impact “Sparing” Yes No ↓ Unnecessary Therapy “Selection” No Yes ↑ Curability Avoid undertreatment “Direction” Equipoise Yes or no More appropriate treatment choices “Confirmation” Yes No Yes No Confirm clinical decision

Rilevanza dell'innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia ricerca traslazionale e la terapia in oncologia

Innovative screening tools: BRCA1/2 mutation screening for hereditary Breast and Ovarian Cancer syndrome hereditary Breast and Ovarian Cancer syndrome Lifetime risk estimates of developing breast and ovarian cancer among h h d women with inherited BRCA1 or BRCA2 mutations Reduction of cancer incidence with surgical and nonsurgical interventions Roukos DH.

Nat Clin Pract Oncol. 2007

Rilevanza dell'innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia ricerca traslazionale e la terapia in oncologia

Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial Marker/Function Variant At Risk GT Drug Effected Hypothesized Impact Activity Toxicity Other py ABCB1/cellular efflux 3435 C to T TT Irinotecan ↓ clearance DPYD/detoxification IVS14 + 1G to A (*2A) Variants Fluorouracil ↑ active metabolite ERCC2/DNA repair 35 931 A to C CC Oxaliplatin ↓ DNA repair ERCC2/DNA repair 35,931 A to C CC Oxaliplatin ↓ DNA repair GSTP1/detoxification 313 A to G AA Oxaliplatin ↓ detoxification MLH1/DNA repair -93 G to A AA Fluorouracil Irinotecan Oxaliplatin ↓ DNA repair Oxaliplatin MTHFR/folate pool, modifies FU response 667 C to T TT Fluorouracil - - TYMS/target for FU metabolite 1494: 6 bp insertion +/+ Fluorouracil ↓ expression metabolite ER: VNTR 28 bp 2R/2R Fluorouracil ↓ expression UGT1A1/detoxification VNTR: 6 or 7 TA repeats (*28) 7/7 Irinotecan ↓ detoxification XRCC1/DNA repair 23 885 G to A AA Irinotecan ↓ DNA repair XRCC1/DNA repair 23,885 G to A AA Oxaliplatin ↓ DNA repair Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of irinotecan treatment Braun MS, et al.

J Clin Oncol. 2009 p g

Rilevanza dell'innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia ricerca traslazionale e la terapia in oncologia

Molecular profiling for individual risk assessment : MammaPrint® (70 genes involved in cancer biology) ( g gy) Van ‘t Veer et al, Nature2002

Rilevanza dell'innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia ricerca traslazionale e la terapia in oncologia

MicroRNAs are endogenous non coding single-stranded RNAs of ~ 22nt that play important roles in animals and plants by targeting 3’UTR of mRNAs for cleavage or translational repression MiRNAs may thus represent one of the largest class of gene regulators They are implicated in a variety of processes, such as development, organogenesis, stemness and differentiation, growth control and programmed cell death

Relationship between the expression levels of 9 MicroRNAs and time from diagnosis to initial therapy in patients with chronic lymphocytic leukemia (CLL) (P

Present and future of targeted therapy Siena S et al,JNCI 2009

Biomarkers discovery: predictive value of EGFR‐activating mutations for anti‐EGFR therapy (lung cancer) EGFR Mutation Positive EGFR Mutation Negative HR: 0.48 ty of PFS 1.0 0.8 0.6 ty of PFS 1.0 0.8 0.6 Events Gefitinib: 97 (73.5%) Pac/carbo: 111 (86.0%) Events Gefitinib: 88 (96.7%) Pac/carbo: 70 (82.4%) (95% CI: 0.36‐0.64; P < .001) Probabilit Gefitinib Paclitaxel/ carboplatin 0.4 0.2 Probabili Gefitinib Paclitaxel/ carboplatin 0.4 0.2 Mos Since Randomization 0 4 8 12 16 20 24 Mos Since Randomization 0 4 8 12 16 20 24 ORR, % Gefitinib Paclitaxel/ P Value ORR, % Gefitinib Paclitaxel/ Carboplatin P Value Overall population 43.0 32.2 < .001 EGFR mutation positive 71 2 47 3 < 001 EGFR mutation positive 71.2 47.3 < .001 EGFR wild type 1.1 23.5 .001 Mok TS, et al.

NEJM 2009

Biomarkers discovery: predictive value of K‐ras status for anti‐EGFR therapy (CRYSTAL trial) K ras status for anti EGFR therapy (CRYSTAL trial) Influence of KRAS status on efficacy of cetuximab plus FOLFIRI Normanno N et al. Nat. Rev. Clin. Oncol 2009

Translational Potential of Protein Microarrays for Routine Use in Clinical Research Specimens Tumor biopsy Microdissection Tumor biopsy Microdissection Protein Microarray Data Analysis Data Analysis Patient/Tumor‐Specific Signaling Network Profile Tailored targeted therapy

Patient A Patient B Patient A Patient B

Pathology Report of the Future: Glioblastoma Mulitforme Patient 1 Glioblastoma Mulitforme Patient 2 Individualized Protein Pathway Activation Maps Glioblastoma Mulitforme Patient 1 Glioblastoma Mulitforme Patient 2

Symmetric division Asymmetric division division division Non tumorigenic differentiated cell Non tumorigenic transient amplifying progenitors Tumorigenic cancer stem cells Non Old view New view x Non New view x Potentially Metastatic x x Potentially Metastatic x x metastatic Non Metastatic metastatic Non Metastatic Metastatic xx x Metastatic xx x

Symmetric division Asymmetric division division division Non tumorigenic differentiated cell Non tumorigenic transient amplifying progenitors Tumorigenic cancer stem cells Non Old view New view x Non New view Potentially Metastatic x x Potentially Metastatic metastatic Non Metastatic metastatic Non Metastatic Metastatic xx x Metastatic x

Symmetric division Asymmetric division division division Non tumorigenic differentiated cell Non tumorigenic transient amplifying progenitors Tumorigenic cancer stem cells Non Old view New view x Non New view x Potentially Metastatic x x Potentially Metastatic x x metastatic Non Metastatic metastatic Non Metastatic Metastatic xx x Metastatic xx x x x

Colon cancer spheres are tumorigenic and reproduce the original tumor even CDX2 beta-catenin CK 20 after long term expansion patient 50 spheres 106 adherent cells 500 spheres m 3 ) 2.0 2.5 Volume (cm 0 5 1.0 1.5 mouse Time (weeks) V 0.5 10 12 14 patient mouse mouse after ½ year mouse after 1 year ( ) H&E Ricci-Vitiani et al. Nature 445:111, 2007

Need for more reliable animal models: CSC‐derived vs cell line‐derived xenografts CSC derived vs cell line derived xenografts Cancer stem cells NCI 60 cell lines RPPM

MRI ISS has the largest collection of cancer stem cells MRI Tumor database Diagnosis and tissue banking Tumor dissociation H&E Cancer stem cell banking dissociation Stem cell culture and expansion g Tumor Type Histotype Total available Glioblastoma ‐ 32 Tumor Type Histotype Total available Colorectal Colon 18 Glioblastoma ‐ 32 Melanoma ‐ 9 Ovary ‐ 3 Breast Infiltrating ductal 9 Infiltrating lobular 1 Colorectal Colon 18 Rectum 8 Squamous 7 Adenocarcinoma 8 Lung Large Cell 5 Thyroid Anaplastic 4 Papillary 8 Follicular 6 Small Cell 2 Carcinoid 1 TBD 3

Translating the CSC concept into clinical studies Banking and characterization of CSCs Identification of druggable pathways T t f th t t d i hibit Identification of druggable pathways through high‐throughput technologies (i.e. RPPM): in vitro drug screening Test of pathway‐targeted inhibitors on CSC‐derived xenografts Clinical studies: R t ti (bi k lid ti ) ‐Retrospective (biomarkers validation) ‐Prospective (adaptive trials)

Rilevanza dell'innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia ricerca traslazionale e la terapia in oncologia
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