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Transcript of Oltre la chemioterapia prof. Giuseppe Naso ONCOLOGIA MEDICA POLICLINICO UMBERTO I prof. Giuseppe...
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Oltre la chemioterapiaOltre la chemioterapia
prof. Giuseppe Naso
ONCOLOGIA MEDICA
POLICLINICO UMBERTO I
prof. Giuseppe Naso
ONCOLOGIA MEDICA
POLICLINICO UMBERTO I
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Recent gene-profiling studies
have nicely confirmed that ER-
positive and ER- negative breast
cancer are essentially two
different disease
M.J.Piccart-Gebhart: JCO vol.21, 8: 2003
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ER+ ER-
HER-2+ ?
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Expression of growth factor receptors in breast cancer
% expression Receptor in breast cancer
KIT 80%
PDGFR 50%-90%
EGFR 14%-91%
EGFR vIII 20%-78%
HER2 20%-25%
HER3 20%-70%
HER4 7%-18%
IGF-IR Induced by estrogen
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EGFTGF
Amphiregulin-cellulinHB-EGF
Epiregulin Heregulins
NRG2NRG3
Heregulins-cellulin
Cysteine-richdomains
Tyrosine kinasedomain
ErbB-1Her1
EGFR
ErbB-2Her2neu
ErbB-3Her3
ErbB-4Her4
C-terminus
100
100
100
44
82
33
36
59
24
48
79
28
The EGFR (ErbB) family and ligands
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R
K
R
K
Cell surface
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R
K
R
K
Cell surface
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R
K
R
K
Cell surface
PI3K
Shc
Grb2 Ras Sos
Raf
MEK1/2
Akt
MAPK
PTEN
GSK-3mTOR FKHR BadIntra-CellularSignaling
NF-
[PI4P,PI4,5 P2][PI3,4P2 PI3,4,5 P3]
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R
K
R
K
Cell surface
PI3K
Shc
Grb2 Ras Sos
Raf
MEK1/2
Akt
MAPK
PTEN
GSK-3mTOR FKHR BadIntra-CellularSignaling
NF-
[PI4P,PI4,5 P2][PI3,4P2 PI3,4,5 P3]
p27
Gene Transcription/Cell Cycle Progression
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R
K
R
K
Cell surface
Survival Proliferation Angiogenesis MetastasisCellular Responses
PI3K
Shc
Grb2 Ras Sos
Raf
MEK1/2
Akt
MAPK
PTEN
GSK-3mTOR FKHR BadIntra-CellularSignaling
NF-
[PI4P,PI4,5 P2][PI3,4P2 PI3,4,5 P3]
p27
Gene Transcription/Cell Cycle Progression
rho
rac
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1 2
K KSHC
PI3KGRB2
SOS
AKT
RAS
PTEN
mTOR FKHR GSK-3 BAD
Cell cicle
progression
Survival
RAF
MEK 1/2
MAP
Anti ErbB1-2 receptors Mabs(Trastuzumab, 2C4, C225)
HER1,HER2,HER4, Tyrosine Kinase Inhibitors (ZD 1839, OSI 774, EKB 559,
GW 2016, CI 1033)
Ras farnesyl transferase Inhibitors (BMS 214662, R115777)
RAF inhibithorsmTOR inhibitors (CCI 779)
Mek inhibitors (CI 1040)
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ERAF1
AF2
ESTRADIOLO
ERE
ERE
ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE
ERTAMOXIFENAF1
AF2
ERE ATTIVAZIONE PARZIALEDELLA TRASCRIZIONE
(solo AF1)
Meccanismo d’azione di Estradiolo e Tam a confronto
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ERAF1
AF2
ESTRADIOLO
ERE
ERE
ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE
ERAF1
AF2
BLOCCO COMPLETODELLA TRASCRIZIONEEs
A.I.FASLODEX
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In most cases AF-1/AF-2 are present in resistant tumours,
and in many of these its activity continues to regulate
tumour growth
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TyrosineKinase
GRB2
SOSras-GDP ras-GTP
raf
MEK
MAPK
ATP
ATP
ATP
forma inattiva Forma attivata
fosmycjun
MAP
La cascata delle chinasi della via rasLa cascata delle chinasi della via ras
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TyrosineKinase
GRB2
SOSras-GDP ras-GTP
raf
MEK
MAPK
ATP
ATP
ATP
forma inattiva Forma attivata
fosmycjun
MAP
La cascata delle chinasi della via rasLa cascata delle chinasi della via ras
AKT
AF
1
COREPRESSORE
COATTIVATORE MAPATP
Hormone-dependent growth
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Che succede se si utilizzano contemporaneamente
un antiestrogeno e un inibitore della TK attivata dagli EGFRs ?
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Effects of ER and EGFR blockade are:
•Reproducible:
Total cell kill has been achieved in 5/6 experiments by 4 months using Tamoxifen and Iressa
•Seen with other anti-hormonal drugs:
Faslodex plus Iressa achieved a total cell kill by 3 months
•Observed in other cell lines:
T47D cells show equivalent early responses
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Role of HER2 in breast cancer
• HER2 gene amplification or receptor overexpression occurs in approximately 25 % of breast cancers
• HER2-positive tumours are associated with poor prognosis
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HER2 status as a prognostic indicator
Univariate Multivariate
Factor Survival Relapse Survival Relapse
No. positivenodes 0.0001 0.0002 0.0003 0.001
HER2 0.0011 <0.0001 0.02 0.001
Log (PR) 0.05 0.05 N/A N/A
Tumour size 0.06 0.06 N/A N/A
Log (ER) 0.15 0.10 0.03 N/A
n=86 node-positive patients/Southern blot assay/median follow-up 46 monthsER = oestrogen receptorPR = progesterone receptor
Slamon DJ et al. Science 1987; 235: 177–182
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HER2 status as a prognostic indicator:Disease-free survival of node-positive breast cancer
patients related to HER2 status
100
80
60
40
20
00 12 24 36 48 60 72
Dis
ease
-fre
e su
rviv
al p
rob
abil
ity
Time (months)
HER2 gene <3 copies
HER2 gene 3 copies
Log rank p=0.001
Seshadri R et al. J Clin Oncol 1993; 11: 1936–1942
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HER2 status as a prognostic indicator:Survival of node-negative breast cancer patients
related to HER2 status
1.00
0.75
0.50
0.25
0
Cu
mu
lati
ve p
rob
abil
ity
0 24 48 72 96 120 144
Not amplified
Amplified
Amplified: >10 copies/nucleusNot amplified: <3 copies/nucleusBorderline: excluded
Time to death (months)
Log rank p<0.001
Ross JS, Fletcher JA. Stem Cells 1998; 16: 413–428
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Expression of growth factor receptors in breast cancer
% expression Receptor in breast cancer
KIT 80%
PDGFR 50%-90%
EGFR 14%-91%
EGFR vIII 20%-78%
HER2 20%-25%
HER3 20%-70%
HER4 7%-18%
IGF-IR Induced by estrogen
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HER hierarchy
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Bivalence of EGF-like ligands
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Relative potency of HER dimers
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HER2-promoted recycling of HER1
cbl
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Eligible patients (n=469)
No prior anthracyclines
Prior anthracyclines
Paclitaxel(n=96)
Trastuzumab + Paclitaxel(n=92)
AC(n=138)
Trastuzumab + AC(n=143)
• Metastatic breast cancer• erbB2 overexpression• No prior chemotherapy for MBC• Measurable disease• KPS ≥60%
Slamon et Al N Engl J Med, March 2001
Herceptin® in breast cancer:what evidence do we have?
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Herceptin® in combinationSummary of benefits
Herceptin® +AC (n=143)
AC alone(n=138)
Herceptin®
+ paclitaxel(n=92)
Paclitaxelalone (n=96)
Herceptin® +chemotherapy
(n=235)Chemotherapyalone (n=234)
Median TTP (months) 8.1 6.1 6.9 3.0 7.6 4.6(p=0.0003) (p=0.0001) (p=0.0001)
Response rate (%) 52 43 42 16 49 32(p=0.1038) (p<0.0001) (p=0.0002)
Median duration of 9.1 6.5 11.0 4.4 9.3 5.9response (months) (p=0.0025) (p=0.0001) (p=0.0001)
Median TTF (months) 7.2 5.6 5.8 2.9 6.9 4.5(p=0.0009) (p=0.0001) (p=0.0001)
1-year survival (%) 83 72 72 60 78 67(p=0.0415) (p=0.0975) (p=0.0080)
TTP = time to disease progressionTTF = time to treatment failure
Slamon DJ at al. 2001os = p 0.05
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Herceptin + Taxani (+/- Platino)TTP (3 studi randomizzati)
3
76,1
10,6
7,2
13,5
0
4
8
12
16
Mes
i
Taxol H+Taxol Taxotere H +Taxotere H+Taxol H+Taxol+Carboplatino
Slamon NEJM 2001 Robert SABCS 2002Marty ECCO 2003
p=0.001
p=0.001p=0.001
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Herceptin + Taxani (+/- Platino)OS (3 studi randomizzati)
Slamon NEJM 2001 Robert SABCS 2002
18
25
18
2830
?
0
12
24
36
Mes
i
Taxol H+Taxol Taxotere H +Taxotere H+Taxol H+Taxol+Carboplatino
Marty ECCO 2003
p=0.5 p=0.001 p=NR
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Goal of the second-generation HER2 programme
For example
Better response rate
Longer duration of response
More clinical benefit in tumours that express intermediate (2+ or 1+) or even low levels (0) of HER2
Develop an agent with clinical activity superior to Herceptin®
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Pertuximab
(2C4)
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Anti-HER2 epitope mapExtracellular domain
CRD-2
Intracellular domain
TK
CT
CRD-1
Bald L, Fendly B
7C2(aa 23–53)
Herceptin®
(aa 529–625)
2C4 Pertuximab(aa 22–584)
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Inhibition of heregulin binding by 2C4, a monoclonal antibody to HER2
Bo
un
d/t
ota
l
2C4 (nM)
0.10
0.08
0.06
0.04
0.02
0.000.1 1 10 100
HER2:HER3
HER3
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Inhibition of ligand binding by 2C4 to HER2-containing receptor complexes
EGFR/HER2 HER3/HER2 HER4/HER2Receptor combination
EGF
HRG HRGRel
ativ
e li
gan
d b
ind
ing
(%
)
100
80
60
40
20
0
Control
2C4
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Effect of Herceptin® or 2C4 on ligand-mediated MAP kinase activation
EGF – + + + – – – – – –
TGF – – – – + + + – – –
HRG – – – – – – – + + +
2C4 – – + – – + – – + –
Herceptin® – – – + – – + – – +
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Summary
In contrast to Herceptin®, 2C4 is very effective in
Blocking HER2 association with other HER family members
Inhibiting HER2 activation and subsequent downstream signalling
suppressing the growth of tumours with ligand-activated HER2
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TC
neo-ANGIOGENESIS
NC
CELL GROWTH
HYPOSSIA(HIF-1 HIF-2)
CELL GROWTH(Apoptotic blockade)
neo-LYNPHOGENESIS
VEGF-A
VEGF-B
VEGF-C
VEGF-D
ONCOGENES ACTIVATION
ONCO-SUPPRESSOR GENES INACTIVATION
MSR – NER – BER - OSR
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The switch to an angiogenic phenotype represent a pivotal step in the multistage process toward malignancy (Folkman 1996)
For solid tumors to grow beyond 1-2 mm3 they require increased access to oxygen and nutrients from the blood supply (Folkman 1971)
1-2 mm3
INTRODUCTION INTRODUCTION
Angiogenesis is required for solid tumor growthAngiogenesis is required for solid tumor growth
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Tumor angiogenesis begins when growing tumors, in response to hypoxia or other stimuli, secrete angiogenic factors
Vascular endotelial growth factor is one of the most potent promoters of angiogenesis and has been identified as a fundamental regulator of tumor neovascolarizzazion
INTRODUCTION INTRODUCTION
Solid tumors stimulate angiogenesis by secreting Solid tumors stimulate angiogenesis by secreting angiogenic factorsangiogenic factors
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INTRODUCTION Tumor angiogenesis promotes tumor growth
and metastasis The creation of new
blood vessels and lymphatic tissue by solid tumors allows them to enlarge and to metastasize to distal sites
Inhibition of tumor angiogenesis, therefore, has the potential to inhibit tumor growth and spread
VEGF levels apper to have prognostic significance in human VEGF levels apper to have prognostic significance in human tumors ( LAM, breast cancer, colon cancer,hepatocellular tumors ( LAM, breast cancer, colon cancer,hepatocellular cancer, NSCLC and ovariancancer, NSCLC and ovarian cancer)cancer)
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The vascular endothelial growth factor (VEGF) family are critical tumor secreted signaling molecules that stimulate angiogenesis and lymphangiogenesis
There are five members of the VEGF family (VEGF-A, placental growth
factor, VEGF-B, VEGF-C,
VEGF-D, VEGF-E) VEGF is a diffusabile
endothelian cell-specific
mitogen pro-angiogenic factor
that increases vascular permeability
VEGF-B
VEGF-A
VEGF-E
VEGF-C
VEGF-D
INTRODUCTIONINTRODUCTION
The VEGF family are critical tumor-secreted The VEGF family are critical tumor-secreted angiogenic factorsangiogenic factors
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VEGFR-1 is activated by VEGF-A and VEGF-B
VEGFR-2 is activated by VEGF-A, VEGF-C, VEGF-D, and VEGF-E
VEGFR-3 is activated by VEGF-C and VEGF-D
Different VEGF family members bind and activate different VEGF receptors on endothelial cells
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•Monoclonal antibody, specific for VEGF A
•Derived from the murine antibody A4.6.1, comprises 93% human antibody and 7% murine derived antigen-binding-protein, the humanization proving a longer half-life and less immunogenicity
•Able to neutralize the biological properties of human VEGF, including endothelian cell mitogenic activity, vascular permeability-enhancing activity and angiogenic properties( Kim K.1992)
•The antibody did not recognize the other growth factor tested including FGF, EGF, PDGF
BEVACIZUMAB (avastin; Genentech)BEVACIZUMAB (avastin; Genentech)
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BEVACIZUMAB: Preclinical StudiesBEVACIZUMAB: Preclinical Studies
Extensive preclinical studies have demonstrated the efficacy in different cell lines subcutaneously injcect into nude mice ( Kim KJ 1993) while did not reveal a direct effect on the growth of tumor cells (Warren RS 1995)
TUMOR SUPPRESSION IS MEDIATED THROUGH INHIBITION OF NEOVASCULARIZZATION
Warren and coworkers demonstrated that treatment with anti-VEGF ab was effective in suppressing primary tumor growth as well liver metastatis growth in a murine model of Colorectal cancer
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BEVACIZUMAB: Clinical StudiesBEVACIZUMAB: Clinical Studies
More than 30 clinical trials with Bevacizumab in solid tumors and More than 30 clinical trials with Bevacizumab in solid tumors and hematologic malignancies are planned, ongoing or recenttly hematologic malignancies are planned, ongoing or recenttly completedcompleted
In general, the therapeutic strategies being evaluated can be In general, the therapeutic strategies being evaluated can be diveded into the following categories:diveded into the following categories:
•Bevacizumab monotherapyBevacizumab monotherapy
•Bevacizumab in combination with chemotherapy or radiotherapyBevacizumab in combination with chemotherapy or radiotherapy
•Bevacizumab in combination with other putative anti-angiogenic Bevacizumab in combination with other putative anti-angiogenic strategies ( low-dose INF, thalidomide..)strategies ( low-dose INF, thalidomide..)
•Bevacizumab in combination with tumor-target therapies ( erlotinib, Bevacizumab in combination with tumor-target therapies ( erlotinib, trastuzumab, imatinib)trastuzumab, imatinib)
•Bevacizumab in combination with immunotherapyBevacizumab in combination with immunotherapy
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Bevacizumab phase I-II clinical trial efficacy results in breast cancer
3mg/kg 10mg/Kg 20mg/Kg Total
N° of Pts 18 41 16 75
Objective Response Rate (n/%) 1 (5.6%) 3 (7.3%) 1 (6.3%) 5 (6.7)
Median Response Duration (months) 3.1 5.6 8.0 5.6
Stable disease at 154 days 2 (11%) 7 (17%) 3 (19%) 12 (16%)
Median Survaival (months) 14.0 12.8 7.6 10.2
Sledge GW et al. JCO 2003
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BEVACIZUMAB:Summary of trials in solid tumorBEVACIZUMAB:Summary of trials in solid tumor
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Inhibition of Ubiquitin-Proteasome pathway
Bortezomib
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L’emivita di una proteina è determinata in gran parte dal suo residuo terminale
Residui altamente stabilizzanti(t1/2 >20 ore)
Ala Cys Gly Met Pro Ser Thr Val
Residui intrinsecamente destabilizzanti(t1/2= da 2 a 390 min.)
Arg His He Leu Lys Phe Trp Tyr
Residui destabilizzanti solo dopo modificazione chimica
Asn Asp Gln Glu
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The Proteasome: Enzyme with Important Impact on Multiple Regulatory Pathways
•Is found in all eukariotic cells, from yeast to man
•Is present in the cytoplasm and nucleus
•Degrades more than 80% proteins
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Tumor microenvironmentExtracellular matrix
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Inibitori di traduzione del segnale:Inibitori di traduzione del segnale:Ras e FT-IRas e FT-I
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NeoplasticTransformation
Inactivation of Rb and p53Immortalization
telomerase activation
Activation of ras-pathway
Weinberg, A. 2003
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Farnesyl-transferase inhibitors
The ras gene is mutated in one fifth of all human cancers.
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RAS
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ras (p21) G-Protein (intrinseca attività GTP-asica)
ras agisce come un interruttore molecolare che sialterna da una forma inattiva (ras-GDP) ad una forma attiva (ras-GTP)
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The switch function of RAS
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TyrosineKinase
GRB2
SOSras-GDP ras-GTP
raf
MEK
MAPK
ATP
ATP
ATP
forma inattiva Forma attivata
fosmycjun
MAP
La cascata delle chinasi della via rasLa cascata delle chinasi della via ras
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Prenilazione
Carbossi-terminale (C-terminale)
CAAX CC – CXC - CCXX
Farnesilazione es.: ras,rho Geranil-geranilazione es.:rab
C=cisteinaA=residui alifaticiX=qualunque aminoacido
Gruppo Farnesile (C15) Gruppo Geranilgeranile (C20)
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C15
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Classes of FTase inhibitors
Peptide CAAX peptidomimetics : L-778,123
Nonpeptide CAAX peptidomimetics : Tipifarnib, Sarosat
Bisubstrate Inhibitors : BMS-214662
Inhibitors classes I
Inhibitors classes II
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Peptide CAAX peptidomimetics : L-778,123
Nonpeptide CAAX peptidomimetics : Tipifarnib, Sarosat
Bisubstrate Inhibitors : BMS-214662
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Phase I-II studies with farnesyl-trasferase inhibitors in clinical development
Drug Company Route RD DLT Activity
R115777 Janssen/ oral 300 mg bid, 7-14 Myelosuppression, 1 PR NSCLCZarnestra Ortho-Biotech fatigue, Tipifarnib neurotoxicity,skin
SCH66336 Schering – Plough oral 350 mg bid, 7-14 Nausea, vomiting, 1 PR NSCLCSarosar diarrhea, fatigue
BMS-214662 Bristol Meyer iv 300 mg/m2 24 h liver, neuropathy -Squibb c.i weekly
L-778,123 Merck iv 560 mg/m2 c.i. 7-14 Myelosuppression, sonnolence, fatigue -
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Tipifarnib (R115777): Phase II clinical trials
Johnston SR.: SABCS 2000
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Combination of 2 selective Combination of 2 selective inhibitors approachinhibitors approach
Combination of 2 selective Combination of 2 selective inhibitors approachinhibitors approach
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EGFR
VEGF
Endothelial cells
Cancer cells
Angiogenesis
Cell Proliferation
Tortora 2004
ErlotinibCetuximab, etc
Bevacizumab etc.
Combined blockade of EGFR and VEGF
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Combined blockade of EGFR and VEGFCombined blockade of EGFR and VEGF
Jung YD et al, Eur J Cancer 2002; 38: 1133-40. Ciardiello F et al. Clin Cancer Res 2000; 6: 3739-3747
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EGFR
VEGF
Endothelial cells Cancer cells
TGF
KDR
Angiogenesis
Cell Proliferation
ZD6474
Tortora & Ciardiello, 2002
ZD6474 Inhibits KDR and EGFR
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ZD6474 is a potent orally-active inhibitor of VEGF-signalling
Inhibits VEGF-induced hypotension, vascular permeability and angiogenesis in vivo
Broad-spectrum anti-tumour activity in mouse models consistent with an anti-angiogenic mechanism
Dosing for > 100 days has been feasible in man
Phase I adverse events generally mild
Anti-VEGF activity suggested by hypertension and delay in dermal wound angiogenesis
ZD6474: Phase I Studies
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0
0,5
1
1,5
2
2,5
3
3,5
0 21 42 63 84 105 126
Giorni
Volu
me
tum
oral
e
0
0,5
1
1,5
2
2,5
3
3,5
0 21 42 63 84 105 126
Giorni
Vo
lum
e tu
mo
ralecontrollo
Gefitinib
Gefitinib >ZD6474
controllo
Cetuximab
Cetuximab > ZD6474
ZD6474 inibisce la crescita di tumori divenuti resistenti a Gefitinib o Cetuximab
Ciardiello et al., 2004
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AZD2171
Enzastaurin
Agents affecting all VEGFRs
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AZD2171
AZD2171 is an oral therapy with potential application in multiple tumor types
AZD2171 has activity against VEGF receptors 1, 2 & 3- No activity on EGFR
Phase I clinical studies in refractory solid tumors underway
Manageable toxicity in early phase I
AZD2171
VEGFR3 (Flt-4)
VEGFR1(Flt-1)
VEGFR2 (KDR)
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Company ConfidentialCopyright © 2004 Eli Lilly and Company
Lilly Research LaboratoriesNot for Promotional USE
NN
NO O
H
Me
N
N
H
Cl-+
MW = 552.08
• Potent oral selective inhibitor of PKC (IC50 = 0.006 M)
• Is an acyclic indolylmaleimide that competes with the ATP binding site preventing substrate phosphorylation
• Inactive against other kinases
• Antiangiogenic activity in preclinical models.
• Well tolerated in preclinical toxicology studies.
• Administered once daily PO. Normal volunteer and Phase I studies completed. Phase II studies ongoing.
Enzastaurin
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Company ConfidentialCopyright © 2004 Eli Lilly and Company
Lilly Research LaboratoriesNot for Promotional USE
Receptor
VEGF
DAG
IP3/Ca2+
PKC-
COX2
mRNA
• Tumor invasion• Angiogenesis
ENZASTAURIN
Activation
GSK3
AKT
Caspase 9
Apoptosis
Protein translationIL-6
IL-8
PKC- and the Proposed Action of Enzastaurin on Angiogenesis and
Apoptosis
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• Pericytes protects endothelial cells from apoptosis and overexpress PDGF-R• PDGF-R is overexpressed by many tumors• PDGF-R and VEGF cooperate
Blood vessels are not only endothelial cells (L.M. Ellis)
Improving Anti-VEGF therapy by expanding the targets
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PTK787
SU11248
Multiple target agents affecting VEGFRs (and PDGF-R)
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• Complete inhibitor of the VEGF receptor tyrosine kinases VEGFR1(FLT-1), VEGFR2 (KDR) and VEGFR3 (FLT-4). It also inhibits PDGF-R.
• Well tolerated up to 1250 mg/day (phase III dose, used up to 15 mo)
• Rapidly absorbed (1 to 2.5 hours), T1/2: 3-6 hrs
• Renal metabolism
PTK787/ZK 222584PTK787/ZK 222584
Formula: C24H21N4Cl MW = 346.82
PTK787/ZK 222584PTK787/ZK 222584
Formula: C24H21N4Cl MW = 346.82
PTK/ZK: A multi-VEGF receptor tyrosine kinase inhibitor
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SU11248 is an Oral, Multi-targeted, RTK Inhibitor With Selective Activity against PDGFR, VEGFR, KIT, and FLT3
Split Kinase Domain RTKs
FLT1FLK1/KDRFLT4
FGFR1FGFR2FGFR3FGFR4
PDGFR
CSF1RKITFLT3/FLK2
PDGFR
Potent Activity vs. Class III, Class V RTKs:Biochemical Ki values <10nMCellular IC50 values 5-50nM
Weak Activity vs. Class IV RTKs:Biochemical Ki values 1000 nMCellular IC50 values 6000 nM
Highly selective for Class III, Class V RTKs, versus other tyrosine kinases and serine/threonine kinases evaluatedClass III Class V Class IV
• Direct anti-tumor activity via inhibition of target RTKs
- VEGFR in Melanoma, PDGFR in Glioma, KIT in GIST, FLT3 in AML
• Indirect inhibition of tumor growth via inhibition of angiogenesis
- VEGFR and PDGFR
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Conclusioni (I)
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Genes changing in associationwith response
Genes changing in associationwith response
Good respondersGood responders Poor respondersPoor responders
14 genes 14 genes sharedshared
biologically biologically responsiveresponsive
biologicallbiologically y
refractoryrefractory
256 genes256 genes256 genes256 genes 49 genes49 genes49 genes49 genes
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Response in patients treated with FAC/paclitaxel preoperative
chemotherapy
Response in patients treated with FAC/paclitaxel preoperative
chemotherapy
Hortobagyi GN ASCO 2002Hortobagyi GN ASCO 2002
150 Genes150 Genes
pCRpCR NoPCRNoPCR
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Conclusioni (II)
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“…A targeted therapy only works when the target is present and plays an important role in the cancer…”
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IRESSA and NSCLC:a very important lesson
No target 10-12% of Response
Target 100% of Response
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Prof. Enrico Cortesidott.ssa A. De Benedetto dott. A. Luginidott. A. Padovani dott.ssa R. Ferraldeschidott.ssa G. D’auria dott. P. Ceratti dott.ssa N. Pizzardi dott.ssa L. Mentucciadott.ssa M. Mazzoli dr. V. Picone
Oncologia Medica B Univ. Di Roma “La Sapienza”