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Direktor Med. Klinik III
Klinikum der Univ. München
Wolfgang Hiddemann
Personalisierte Medizin (Onkologie)
in der Klinik
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Definition(modifiziert nach: wikipedia, April 2011)
Personalisierte Medizin ist ein Konzept, das die
Patientenorientierung der medizinischen
Versorgung betont.
Alle Entscheidungen und Anwendungen sind
nach Möglichkeit auf die individuellen Bedürfnisse
zugeschnitten.
In jüngster Zeit beinhaltet dies die systematische
Verwendung von genetischen Informationen über
einen individuellen Patient, um dessen präventive
oder therapeutische Versorgung zu optimieren.
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Entstehung einer Krebskrankheit
Normal- Krebs
gewebe
Wachstum
Differenzierung
Zelltod
Gleichgewicht Un-Gleichgewicht
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Onkogene
(Regulation von
Wachstum)
Tumorsuppressorgene
(Korrektur- und
Kontrollgene)
Entstehung einer Krebskrankheit
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Chronische myeloische Leukämie
Philadelphia-Chromosom
Zytogenetik:
Translokation t(9 ; 22)
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bcr-ablTyrosin-kinase
Sub-strat
Tyr
ATP
P
ADP
Veränderte Zell-Adhäsion Abnormales Wachstum Apoptosehemmung
Leukämie (CML)
Philadelphia-Chromosom: t(9;22) Bcr-abl-Fusionsprotein Dauer-aktive Tyrosinkinase Leukämie
Translokation t(9;22)
Zellmembran
Substrate sind verschiedene Signalproteine:
Crkl PI3K Ras Raf MAPK Src-Kinasen
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Sub-strat
Tyr
ATP
Imatinib
bcr-ablTyrosin-kinase Sub-
strat
Tyr
ATP
P
ADP
Leukämie (CML) Blockiert ATP-Bindungsstelle
Hemmung der Bcr-abl-Kinase durch Imatinib
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Imatinib versus Kombinationstherapie
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Analyse des Krebsgenoms
Auflösung der ungeheuren Komplexität der
Krebsentstehung durch umfassende genetische Analytik
und vertieftes Verständnis der Pathogenese
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Aktuelle Situation in der Krebs- Biologie
Zunehmende Einblicke in die Biologie und Pathogenese von spezifischen Krebserkrankungen
Zunehmende Anzahl von nachweisbaren genetischen Aberrationen
Erhebliche biologische und klinische Heterogenität innerhalb einzelnen Tumor-Entitäten
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Genomische Landkarte
eines Kolorektalen Karzinoms
80 mutations in one carcinoma (individual genome of every carcinoma)
Wood LD et al. (2007) Science 318: 1108-1113
Sequence analysis of 20857 transcripts of 18191 genes
Testset: 11 colon carcinomas; Validation: 24 + 96 colon
carcinomas
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Klicken Sie, um die Formate des Gliederungstextes zu bearbeiten
Zweite Gliederungsebene
Dritte Gliederungsebene
(Jones et al., Science
2008)
Alteration weniger zentraler
Signalübertragungswege
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The key understanding of cancer lies in the
appreciation of a core set of pathways and
processes
The pathway components that are altered in any
individual tumor vary widely
The pathway perspective helps to bring order and
rudimentary understanding to a very complex
disease
The best hope for therapeutic development may lie
in the discovery of agents that target the
physiologic effects of the altered pathways and
processes rather than their individual gene
components
Jones et al. (2008) Science 321: 1801
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Paradigmen-Wechsel in der
onkologischen Diagnostik und Therapie
Gestern
Tumor definiert durch Lokalisation und Gewebspathologie
Mammakarzinom
Bronchialkarzinom
Pankreaskarzinom
Therapie durch Stahl, Strahl, Chemotherapie
Morgen Tumor definiert durch
molekulare Signatur
„RAS-Typ“„AKT/PTEN“-TypEGFR-Mutation„p53“-Typ
Molekulare Behandlung PersonalisiertBasierend auf Verständnis
der Pathogenese
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Therapie-erfolg
TumorgewebeMolekulare Diagnose
Signatur Signalweg 1“gute Prognose”
Signatur Signalweg 2“schlechte Prognose”
Medikament 2Medikament 1
Therapie-erfolg
Therapieversagen
Medikament 3 oder Chemotherapie etc.
periph. Blut
Paradigmen-Wechsel in der
onkologischen Diagnostik und Therapie
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#
1
1
#1
3
#
5
A
B
Morphologie Zytogenetik
PCR
FISH 24 Color FISH
MFC Gen Expression
Obligate molekulare (und genetische)
Diagnostik
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Akute Myeloische Leukämie
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balanced Aberrations (25%)
t (8;21); t (15;17); inv 16
un-balanced Aberrations (27%)
- 5,5q-; 7q-; complex Karyotype
including
NPM Mutations (62%)
FTL 3 Length-Mutations (35%)
MLL Tandem-Duplications (5%)
C/EBP Mutations (8-10%)
aberrant
(52%)
non-
aberrant
(48%)
AML Karyotyp
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AML Karyotyp
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WT27.50%
NPM1+28.39%
FLT3-ITD+
5.36%FLT3-TKD+
0.89%
MLL-PTD+4.64%
CEBPA+4.82%
NPM1+/FLT3-ITD+18.75%
NPM1+/FLT3-TKD+3.04%
NPM1+/CEBPA+0.36%
FLT3-ITD+/FLT3-TKD+0.36%
FLT3-ITD+/MLL-PTD+1.96%
FLT3-ITD+/CEBPA+1.07%
FLT3-TKD+/MLL-
PTD+0.54%
MLL-PTD+/CEBPA+0.18%
NPM1+/FLT3-ITD+/FLT3-TKD+0.89%
NPM1+/FLT3-ITD+/MLL-PTD+0.18%
NPM1+/FLT3-ITD+/CEBPA+0.71%
NPM1+/FLT3-TKD+/CEBPA+0.36%
AML - Biologische Subgruppen
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AML - Risikogruppen
balanzierte Translokationen
t (8;21); t (15;17); inv 16
normaler Karyotyp und NPM1 mut.
-5,5q-; 7q-; komplexe Aberrationen;
3(q21,q26), 11(q23), FLT3 mut., MLL
ITD
andere zytogenetische Aberrationen
normaler Karyotyp ohne NPM1
und/oder FLT3 mut. oder MLL ITD
niedrig
hoch
intermediär
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Gastro Intestinaler Stroma Tumor
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GIST
Verweij J et al. Lancet 2004;364:1127-34.
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GIST - KIT Mutationen
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Debiec-Richter M et al., Eur J Cancer, 2006
GIST - KIT Exon 9 und 11 Mutationen
Imatinib 800 mg
Imatinib 400 mg
Imatinib 400 mg
Imatinib 800 mg
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Metastasiertes Kolon Karzinom
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Anti-EGFR-Antikörper
28 BMS-ASCO-CRC-Therapy-Ellis
Camp et al, Clin Cancer Res 2005
SrcA
ctPI-3K
AktMu
t
NucleusNucleus
EGFR MoAB
EGFR
Fak
RasM
ut
RafM
ut
MEK
Erk
PTENM
ut/Inact
ivaed
Survival Pathway Proliferativer
Pathway
40% CRC mutiert
Mut
aktivierende Mutationen
Codons 12, 13 (90%)
Codons 61, 63 (10%)
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EGF
TGF
Heregulins
NRG2
NRG3
Heregulins
Tyrosinkinasen-
Domäne
erbB-1
HER1
EGFR
erbB-2
HER2
neu
erbB-3
HER3
erbB-4
HER4
C-Terminus
100
100
100
44
82
33
36
59
24
48
79
28
Antikörper und Tyrosinkinase-Inhibitoren
gegen Tumorzell - Rezeptoren
Cetuximab
ErlotinibGefitinib
Trastuzumab
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Lambrecht D, et al. ASCO 2009
Häufigkeit von KRAS, BRAF, NRAS und PIK3CA
Mutationen beim Kolon Karzinom
Häufigkeit der
Mutationen
PFS: HR (WT vs Mutation)
P-Wert
KRAS 36.5% 0.542 <0.001
BRAF 5% 0.410 <0.001
PI3K (bei KRAS WT)
6% 0.848 0.338
KRAS
BRAF
PI3K
13% 0.538 <0.001
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Lambrecht D, et al. ASCO 2009
CRYSTAL Studie:FOLFIRI
FOLFIRI + Cetuximab
R
KRAS-Wildtyp FOLFIRIFOLFIRI + Cetuximab
P-Wert
N 350 316
Ansprechrate 40% 57% <0.0001
Medianes PFS (Mo) 8.4 9.9 0.0012
Medianes OS (Mo) 20.0 23.5 0.0094
KRAS-Mutation FOLFIRIFOLFIRI + Cetuximab
P-Wert
N 183 214 -
Ansprechrate 36% 31% -
Medianes PFS (Mo) 7.7 7.4 -
Medianes OS (Mo) 16.7 16.3 -
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Pathologische Diagnostik
KRAS-Mutation 40% KRAS-Wildtyp 60%
Bevacizumab1st- / 2nd-line
Cetuximab
1st- / 2nd-line
Bevacizumab1st- / 2nd-line
Panitumumab3rd-line
Kolon Karzinom - Therapiekonzepte
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Initiale Diagnostik
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Nicht Kleinzelliges Bronchial Karzinom
Überexpression von EGFR
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Epidermal Growth Factor Rezeptor
(EFGR)-Mutationen beim NSCLCReceptor L-domain
Receptor L-domain
Furin-like domain
Kinase domain
Transmembrane regionE18
E19
E20
E21
Substitutions
In-frame deletions
Duplications/insertionsSubstitutions
Substitutions (L858R)
6%
~480 / 2500 (20%) mutation positive
6%
46%
42%
Modified from T. Lynch, Boston
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EGF
TGF
Heregulins
NRG2
NRG3
Heregulins
Tyrosinkinasen-
Domäne
erbB-1
HER1
EGFR
erbB-2
HER2
neu
erbB-3
HER3
erbB-4
HER4
C-Terminus
100
100
100
44
82
33
36
59
24
48
79
28
Antikörper und Tyrosinkinase-Inhibitoren
gegen Tumorzell - Rezeptoren
Cetuximab
ErlotinibGefitinib
Trastuzumab
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EGFR mutations
8/9
0/7
Gefitinib responders
Non-responders
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EGFR-Mutationen und Outcome(IPASS trial, Tony Mok, NEJM 2009)
Gefitinib, HR=0.19, 95% CI 0.13, 0.26, p<0.0001No. events M+ = 97 (73.5%)No. events M- = 88 (96.7%)Carboplatin / paclitaxel, HR=0.78, 95% CI 0.57, 1.06, p=0.1103No. events M+ = 111 (86.0%)No. events M- = 70 (82.4%)
0 4 8 12 16 20 24
Time from randomisation (months)
0.0
0.2
0.4
0.6
0.8
1.0Probabilityof PFS
Gefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129)Carboplatin / paclitaxel EGFR M- (n=85)
Hazard ratio <1 implies a lower risk of progression in the M+ group than in the M- groupM+, mutation positive; M-, mutation negative
Slide courtesy of Tony Mok, Hongkong
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Praxis-relevante Beispiele für eine
individuelle, zielgerichtete
KrebstherapieKrankheit Diagnostisches
GenZielprotein Medikament
CML Bcr-Abl (Philadelphia-Chromosom)
Abl-Kinase Imatinib, Dasatinib, Nilotinib
Kolon-Karzinom K-Ras (unmutiert!)
EGF-Rezeptor Cetuximab, Panitumumab
Nicht-kleinzelliges Bronchial-karzinom
EGF-Rezeptor-Mutationen
EGF-Rezeptor Erlotinib (Tarceva®)
Gefitinib (Iressa®)
Akute Promyelozytenleukämie (AML M3)
PML-RARalpha Retinsäure-rezeptor alpha
All-trans-Retinsäure (ATRA)
Brustkrebs Her2neu (Protein) Her2neu Herceptin
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Die Onkologie der Zukunft Personalisierte, „highly active anti-cancer
therapy“ (HAACT)
• Hochdifferenzierte, molekulare Diagnostik
• Analyse defekter Signalwege
• Entwicklung individueller Konzepte zur Prognose und Therapie für jeden Tumor und Patient
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COMPACT “Common Pathways for Cancer Therapy”
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Biologic
Features
Acute Leukemia
Clinical
Features
Characterization
of
Pathway
Alterations
LymphomaPancreatic CancerColon Cancer
Identification
of
Common
Pathways
Cross-Tumor
Target
Evaluation
Perspectives:
Pathway Alteration Screening and Biomarker Development
Definition of Biologic Tumor Subtypes
Cross Tumor Assessment of New/Old Agents
Preclinical Testing in Disease Models
New Clinical Trials
Translation
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TumorTherapie
Lebens-
qualität
Patient Arzt
Gesundheitssystem
Personalisierte Medizin
![Page 43: Personalisierte Medizin (Onkologie) in der Klinik...individual tumor vary widely The pathway perspective helps to bring order and rudimentary understanding to a very complex disease](https://reader033.vdokument.com/reader033/viewer/2022041807/5e5539e5ecb2cb68fc5f0d4d/html5/thumbnails/43.jpg)
TumorTherapie
Lebens-
qualität
Patient Arzt
Gesundheitssystem
ÖkonomieLeit-
linienMDK
Personalisierte Medizin
![Page 44: Personalisierte Medizin (Onkologie) in der Klinik...individual tumor vary widely The pathway perspective helps to bring order and rudimentary understanding to a very complex disease](https://reader033.vdokument.com/reader033/viewer/2022041807/5e5539e5ecb2cb68fc5f0d4d/html5/thumbnails/44.jpg)
TumorTherapie
Lebens-
qualität
Patient Arzt
Gesundheitssystem
ÖkonomieLeit-
linienMDK
Personalisierte Medizin
![Page 45: Personalisierte Medizin (Onkologie) in der Klinik...individual tumor vary widely The pathway perspective helps to bring order and rudimentary understanding to a very complex disease](https://reader033.vdokument.com/reader033/viewer/2022041807/5e5539e5ecb2cb68fc5f0d4d/html5/thumbnails/45.jpg)