Rilevanza dell'innovazione tecnologica per la ricerca traslazionale e la terapia in oncologia - Ruggero De Maria
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Rilevanza dell’innovazione tecnologica per la
ricerca traslazionale e la terapia in oncologia
Ruggero De Maria
Dipartimento di Ematologia Oncologia e Medicina Molecolare,
Istituto Superiore di Sanità
Translational research:
the central role of biotechnologies
Clinicians Bench scientists Clinical scientists
Pathophysiology Genomics Clinical trials
Diseases Proteomics
New infections Stem cells
Transgenic/knockouts
Structural
biology/Imaging
Clinical problem Clinical application
Association of molecular markers with toxicity outcomes in a randomized
trial of chemotherapy
py for advanced colorectal cancer: the FOCUS trial
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 Yes Confirm clinical decision
No No
Innovative screening tools: BRCA1/2 mutation screening for
hereditary Breast and Ovarian Cancer syndrome
Lifetime risk estimates of
developing breast and
ovarian cancer among
women with h inherited
h d
BRCA1 or BRCA2 mutations
Reduction of cancer
incidence with surgical
and nonsurgical
interventions
Roukos DH. Nat Clin Pract Oncol. 2007
Association of molecular markers with toxicity outcomes in a randomized
trial of chemotherapy
py for advanced colorectal cancer: the FOCUS trial
Hypothesized Impact
Marker/Function Variant At Risk GT Drug Effected
Activity Toxicity Other
ABCB1/cellular efflux 3435 C to T TT Irinotecan ↓ ↑ ↓ clearance
IVS14 + 1G to A
DPYD/detoxification Variants Fluorouracil ↓ ↑ ↑ active metabolite
(*2A)
ERCC2/DNA repair 35 931 A to C
35,931 CC Oxaliplatin ↓ ↑ ↓ DNA repair
GSTP1/detoxification 313 A to G AA Oxaliplatin ↓ ↑ ↓ detoxification
Fluorouracil
MLH1/DNA repair -93 G to A AA Irinotecan ↓ ↑ ↓ DNA repair
Oxaliplatin
MTHFR/folate pool, modifies
667 C to T TT Fluorouracil ↓ ↑ --
FU response
TYMS/target for FU 1494: 6 bp insertion +/+ Fluorouracil -- ↑ ↓ expression
metabolite ER: VNTR 28 bp 2R/2R Fluorouracil -- ↑ ↓ expression
VNTR: 6 or 7 TA
UGT1A1/detoxification 7/7 Irinotecan ↓ ↑ ↓ detoxification
repeats (*28)
Irinotecan
XRCC1/DNA repair 23 885 G to A
23,885 AA ↓ ↑ ↓ DNA repair
Oxaliplatin
Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for
neutropenia
p followingg initiation of irinotecan treatment
Braun MS, et al. J Clin Oncol. 2009
Molecular profiling for individual risk assessment :
MammaPrint® ((70 genes
g involved in cancer biology)
gy)
Van ‘t Veer et al, Nature2002
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 deathRelationship between the expression levels of 9 MicroRNAs and time from diagnosis
to initial therapy in patients with chronic lymphocytic leukemia (CLL)
((PPresent and future of targeted therapy
Siena S et al,JNCI 2009Biomarkers discovery: predictive value of
EGFR‐activating mutations for anti‐EGFR therapy (lung cancer)
EGFR Mutation Positive EGFR Mutation Negative
1.0 Events 1.0
Gefitinib: 97 (73.5%) Events
Probability of PFS
Probabilitty of PFS
0.8 Pac/carbo: 111 (86.0%) 0.8 Gefitinib: 88 (96.7%)
0.6 HR: 0.48 0.6 Pac/carbo: 70 (82.4%)
(95% CI: 0.36‐0.64; P < .001)
0.4 0.4
Paclitaxel/ Gefitinib Paclitaxel/
0.2 carboplatin
0.2
carboplatin
Gefitinib
0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Mos Since Randomization Mos Since Randomization
ORR, % Gefitinib Paclitaxel/ P Value
Carboplatin
Overall population 43.0 32.2 < .001
EGFR mutation positive 71 2
71.2 47 3
47.3 < .001
001
EGFR wild type 1.1 23.5 .001
Mok TS, et al. NEJM 2009Biomarkers discovery: predictive value of
K‐ras
K ras status for anti
anti‐EGFR
EGFR therapy (CRYSTAL trial)
Influence of KRAS status on efficacy of cetuximab plus FOLFIRI
Normanno N et al. Nat. Rev. Clin. Oncol 2009Translational Potential of Protein Microarrays
for Routine Use in Clinical Research Specimens
Tumor biopsy Microdissection
Protein Microarray
Data Analysis
Patient/Tumor‐Specific
Signaling Network Profile
Tailored targeted therapyPatient A Patient B
Patient A
Patient BPathology Report of the Future:
Individualized Protein Pathway Activation Maps
Glioblastoma Mulitforme Patient 1 Glioblastoma Mulitforme Patient 2Symmetric Asymmetric
division division
Tumorigenic Non tumorigenic transient Non tumorigenic
cancer stem cells amplifying progenitors differentiated cell
Old view New view
x Non
Metastatic
x
xx x
Potentially
metastatic
xx x Non
xx x x Metastatic
x x
xx xSymmetric Asymmetric
division division
Tumorigenic Non tumorigenic transient Non tumorigenic
cancer stem cells amplifying progenitors differentiated cell
Old view New view
x Non
Metastatic
x
xx x
Potentially
metastatic
xx x Non
xx x x Metastatic
x x
xx xSymmetric Asymmetric
division division
Tumorigenic Non tumorigenic transient Non tumorigenic
cancer stem cells amplifying progenitors differentiated cell
Old view New view
x Non
Metastatic
x
xx x
Potentially
metastatic
xx x Non
xx x x Metastatic
x
xxx x
xxColon cancer spheres are tumorigenic
and reproduce the original tumor even
after long term expansion
CDX2 beta-catenin CK 20
2.5
500 spheres
50 spheres
2.0 106 adherent cells
m3)
patient
Volume (cm
1.5
1.0
V
05
0.5
mouse
0
0 2 4 6 8 10 12 14
Time ((weeks))
patient mouse mouse after ½ year mouse after 1 year
H&E
Ricci-Vitiani et al. Nature 445:111, 2007Need for more reliable animal models:
CSC‐derived
CSC derived vs cell line‐derived
line derived xenografts
Cancer stem cells
NCI 60 cell lines
RPPMISS has the largest collection of cancer stem cells
MRI
Diagnosis and Tumor
tissue banking database
H&E
Tumor
dissociation
Stem cell culture
and expansion
Cancer stem cell
bankingg
Tumor Type Histotype Total available Tumor Type Histotype Total available
Colorectal Colon 18 Glioblastoma ‐ 32
Rectum 8 Melanoma ‐ 9
Squamous 7 Ovary ‐ 3
Adenocarcinoma 8 Breast Infiltrating ductal 9
Lung Large Cell 5 Infiltrating lobular 1
Small Cell 2 Anaplastic 4
Carcinoid 1 Thyroid Papillary 8
TBD 3 Follicular 6Translating the CSC concept into clinical studies
Banking and characterization of CSCs
Identification of druggable pathways TTestt off pathway‐targeted
th t t d inhibitors
i hibit
through high‐throughput technologies on CSC‐derived xenografts
(i.e. RPPM): in vitro drug screening
Clinical studies:
‐Retrospective
R t ti (biomarkers
(bi k validation)
lid ti )
‐Prospective (adaptive trials)You can also read
