University of MilanoBicocca, Monza, Italy
Monoclonalita’ dei tumori:
Studio della Glucosio 6PDeidrogenasi (G6PD) in pazientifemmine
University of MilanoBicocca, Monza, Italy
Incidence of Incidence of HematologicHematologic MalignanciesMalignancies
Type of LeukemiaType of Leukemia Incidence per Incidence per 100,000*100,000*
Overall Overall 66––1010CMLCML 11––22CLLCLL 22––33AMLAML 22––33ALLALL 11––22
University of MilanoBicocca, Monza, Italy
Incidenza = nuovi casi/10E5 anno
Prevalenza = incidenza x sopravvivenza media
University of MilanoBicocca, Monza, Italy
Typical Laboratory Parameters Typical Laboratory Parameters by Phase of CMLby Phase of CML
ParameterParameter ChronicChronic AcceleratedAccelerated BlasticBlasticWBC countWBC count >>20 x 1020 x 1099/L/L —— ——BlastsBlasts 3%3%––10%10% >>15% 15% >>30%30%
BasophilsBasophils ↑↑ >>20% 20% ——PlateletsPlatelets ↑↑or normalor normal ↓↓ or or ↑↑ ↓↓
Bone marrowBone marrow Myeloid hyperplasia Myeloid hyperplasia CytogeneticsCytogenetics Ph+Ph+BcrBcr--AblAbl ++ ++ ++
University of MilanoBicocca, Monza, Italy
CML: Peripheral Blood SmearCML: Peripheral Blood Smear
CMLHoffbrand AV, Pettit JE, eds. In: Color Atlas of Clinical Hematology. 2nd ed. Mosby-Wolfe; 1994:198.
University of MilanoBicocca, Monza, Italy
Clinical Presentation of CMLClinical Presentation of CML
Common SymptomsCommon Symptoms Common SignsCommon SignsFatigueFatigue Palpable Palpable splenomegalysplenomegalyWeight loss/anorexiaWeight loss/anorexiaAbdominal fullnessAbdominal fullness
Common Laboratory FindingsCommon Laboratory FindingsAbnormal differentialAbnormal differential AnemiaAnemiaLeukocytosisLeukocytosis BasophiliaBasophiliaThrombocytosisThrombocytosis
University of MilanoBicocca, Monza, Italy
Epidemiology of CMLEpidemiology of CML
Median age range at presentation: 45 to Median age range at presentation: 45 to 55 years55 years
Incidence increases with ageIncidence increases with age-- 12%12%––30% of patients are >60 years old30% of patients are >60 years old
MaleMale--toto--female ratiofemale ratio——1.3:11.3:1
University of MilanoBicocca, Monza, Italy
Clinical Course: Phases of CMLClinical Course: Phases of CML
Chronic phase
Median 4–6 years stabilization
Accelerated phase
Median duration up to 1 year
Blastic phase (blast crisis)
Median survival 3–6 months
Terminal phase
Advanced phases
University of MilanoBicocca, Monza, Italy
The Philadelphia Chromosome: The Philadelphia Chromosome: t(9;22) Translocationt(9;22) Translocation
22
bcr
abl
Ph
bcr-abl
FUSION PROTEIN WITH TYROSINE KINASE ACTIVITY
9 9+
University of MilanoBicocca, Monza, Italy
CytogeneticCytogenetic Abnormality of CML:Abnormality of CML: The Philadelphia ChromosomeThe Philadelphia Chromosome
University of MilanoBicocca, Monza, Italy
BcrBcr--AblAbl Signal Transduction Signal Transduction PathwaysPathways
Adapted from Pasternak G et al. J Cancer Res Clin Oncol. 1998;124:643-660.
Bcr-Abl
BCL 2inhibition of apoptosis
MYC GRB2 CRKL CBL (p120CBL)
RAS
RAF-MEK-MAPK cascaderegulates cell cycle progression and differentiation
activates
JAK/STATs
upregulation of
Paxillin (Adhesion) PI-3 kinase
Actin (Adhesion)
University of MilanoBicocca, Monza, Italy
M
692 bp501 bp
Patie
nt E
.L.
BaF
3-T/
P
CNeg
ativ
e Pa
tient
TMHLH TKD
308 bp
533 bp
B.
C.
501 bp692 bp
M 10-1 10-2 10-3 10-4 10-5 10-6 CU
University of MilanoBicocca, Monza, Italy
IMATINIB IMATINIB
Tyrosine Tyrosine KinaseKinase InhibitorInhibitorfor CMLfor CML
University of MilanoBicocca, Monza, Italy
Structure Structure of imatinibof imatinib
Class: Class: PhenylaminopyrimidinesPhenylaminopyrimidines, 589.7 mw, 589.7 mw
CH3 SO3 H
O
University of MilanoBicocca, Monza, Italy
Effect of STI571 on Growth ofEffect of STI571 on Growth of BcrBcr--AblAbl––Positive and Positive and ––Negative Cell LinesNegative Cell Lines
Adapted from Gambacorti-Passerini C et al. Blood Cells Mol Dis. 1997;23:380.
*Bcr-Abl-negative cell lines†Bcr-Abl-positive cell lines
U937*KG1*KCL22*K562†
KU812†
SU DHL1†
STI571 Concentration (μM)
% Control CPM
0 0.1 0.3 1 3 10
0
20
40
60
80
100
120
University of MilanoBicocca, Monza, Italy
0102030405060708090
100
0 10 20 30 40 50days
tumor free survival
ctrl3x50 mg/kg i.p.3x160 mg/kg p.o.
University of MilanoBicocca, Monza, Italy
Chronic Phase patients
30.00
20.00 23.08
45.16
32.0028.57
44.83
30.00
96.77
76.9280.00
70.0073,68
54.84 55.17
71.43 68.00
3.230.00
20.00
40.00
60.00
80.00
100.00
0 3 6 9 12 15 18 21 24
Therapy, month
% p
atie
nts
% pt without response % pt with major or complete response
University of MilanoBicocca, Monza, Italy
MCyR within <=3 mthsMCyR within >3-6 mthsMCyR within >6-12 mthsMCyR later than 12 mths
= Censored observations
% w
ithou
t los
s of
MC
yR
0102030405060708090
100
Months since MCyR0 6 12 18 24 30 36 42 48 54 60 66
University of MilanoBicocca, Monza, Italy
Annual Event Rates in Patients After Achievement Annual Event Rates in Patients After Achievement of CCyR on Firstof CCyR on First--line Imatinibline Imatinib
Year afterachieving CCyR All events* AP/BC
1st 5.5% 2.1%2nd 2.3% 0.8%3rd 1.1% 0.3%4th 0.4% 0%
* All deaths or loss of response* All deaths or loss of response includingincluding progression to AP/BCprogression to AP/BC
University of MilanoBicocca, Monza, Italy
Without CML-related deathsOverall Survival
% a
live
0102030405060708090
100
Months since randomization0 6 12 18 24 30 36 42 48 54 60 66
Overall Survival on FirstOverall Survival on First--line Imatinib (ITT line Imatinib (ITT principle) principle)
10.6%4.6% (2-7)
(8-14)
Estimated rate at 60 months (with 95%CI)CMLCML--related deaths related deaths All deathsAll deaths
95.4%89.4%
Survival without CMLSurvival without CML--related deaths related deaths
University of MilanoBicocca, Monza, Italy
Decreasing residual leukemia
Num
ber of leukemia cells (log
10 )
0
1
2
3
4
5
6
7
8
9
10
11
12
13
0
6.0
5.0
4.0
3.0
1.0
0
Log
redu
ctio
n fr
om b
asel
ine Leukocytosis
RQ-PCR positive
RQ-PCR negative
Ph-chromosome pos
Ph-negative but…
Cure ?
BCRBCR--ABL transcript numbers expressed as ABL transcript numbers expressed as log reduction in patients responding to treatmentlog reduction in patients responding to treatment
2.0
University of MilanoBicocca, Monza, Italy
Shc
Ras
Raf
MEK
ERK
Jak
Stat
PI3K
Akt
SCF SCF
Cell membraneKIT KIT
Apoptosis inhibition Proliferation
SHP2Grb2 SOS
NF1
pp90 rsk
Src
Mast Cell Neoplasms
GISTs
816
502-503 550-586 642 822
NH2 COOH
TM JM TK-I KI TK-IIEC
Human Kit
820
Germ cell tumors
820
816557 820 822
University of MilanoBicocca, Monza, Italy
EXPRESSION
EXPRESSION
CAUSAL RELATIONSHIP TO TRANSFORMATION
RELEVANT TARGET FOR THERAPY
HIGHER INTEGRATION BETWEEN LABORATORY AND CLINICAL ACTIVITY NEEDED
University of MilanoBicocca, Monza, Italy
TYPE MOLECULAR PATHOGENESIS KNOWN
TARGETABLE ABNORMALITIES
AVAILABILITY OF SPECIFIC DRUGS
EXAMPLES
I
II
III
IV
YES
YES
YES
NO
YES
YES
NO
?
YES
NO
NO
NO
CML, GIST
Medullary Thyroid Carcinoma
Ewing’s Sarcoma
Melanoma, many Epithelial Cancers
Basic Research
Translational Research
University of MilanoBicocca, Monza, Italy
Indica la definizione NON corretta:a. IPERGLICEMIA: aumento del glucosio nel sangue oltre i valori normali
b. POLIDIPSIA: aumento della sete c. POLIFAGIA: aumento della fame d. GLICOSURIA: presenza di glucosio nel sangue e. POLIURIA: aumento del volume delle urine
Indica la definizione corretta:a. Somatostatina: ormone che stimola la produzione di insulina e glucagone
b. Glucagone: ormone prodotto dalle cellule Delta c. Insulina: ormone prodotto dalle cellule Beta d. Pancreas: ghiandola esocrina e. Glicemia: quantità di glucosio presente nelle urine
La maturazione dell’insulina avviene in diversi compartimenti cellulari e secondo un dato ordine. Indica la sequenza corretta:
a. Pre-proinsulina nel Golgi, Proinsulina nel RER, insulina nel citosol;b. proinsulina nel RER, Pre-Proinsulina nel RER, insulina nel citosol;c. X Pre-proinsulina nel RER, Proinsulina nel Golgi, insulina nelle vescicole di
secrezione;d. Pre-proinsulina nel RER, Proinsulina nel citosol, insulina nelle vescicole di
secrezione;
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