Samenvatting Moleculaire Oncologie
1
,Les 1: Doelgerichte therapieën .......................................................................... 8
Inleiding ............................................................................................................................................... 8
Hallmarks of cancer ......................................................................................................................................... 8
Behandeling .................................................................................................................................................... 8
Definities ......................................................................................................................................................... 9
Gefractioneerd toedienen ............................................................................................................................. 10
Doelgerichte kankerbehandeling....................................................................................................... 10
Algemeen: definitie ....................................................................................................................................... 10
Doelgerichte therapie ................................................................................................................................................ 10
Definities .................................................................................................................................................................... 11
Ideale targets ............................................................................................................................................................. 11
Aangrijpingspunten van doelgerichte therapie............................................................................................. 12
Hormonale therapie................................................................................................................................................... 12
Signaaltransductie ..................................................................................................................................................... 13
Monoklonale antilichamen ........................................................................................................................................ 13
Tyrosinekinase inhibitoren......................................................................................................................................... 15
Angiogene therapie ................................................................................................................................................... 15
Uitdagingen van doelgerichte therapie......................................................................................................... 15
Voorbeeld doelgerichte therapie: de EGFR-pathway als aangrijpingspunt....................................... 16
Algemeen: de EGFR pathway ........................................................................................................................ 16
Anti-EGFR therapie ........................................................................................................................................ 17
Tyrosine kinase inhibitoren (TKI) ............................................................................................................................... 17
Monoklonale antilichamen ........................................................................................................................................ 17
Biomerkers ......................................................................................................................................... 18
Types biomerkers .......................................................................................................................................... 18
biomerker voor aanleg............................................................................................................................................... 18
screeningsbiomerker ................................................................................................................................................. 18
diagnostische biomerkers .......................................................................................................................................... 19
prognostische biomerkers ......................................................................................................................................... 19
predictieve biomerkers .............................................................................................................................................. 19
farmacodynamische biomerker ................................................................................................................................. 20
herval biomerker ....................................................................................................................................................... 20
uitdagingen biomerkers ............................................................................................................................................. 20
EGFR en KRAS als biomerker ......................................................................................................................... 20
EGFR ALS BIOMERKER ................................................................................................................................................ 20
KRAS ........................................................................................................................................................................... 21
Les 2: angiogenese ........................................................................................... 22
HIF activeert angiogene factoren ...................................................................................................... 22
2
, algemeen ....................................................................................................................................................... 22
HIF1: hypoxie-induceerbare factor ............................................................................................................... 23
structuur HIF1 ............................................................................................................................................................ 23
Proces HIF1 ................................................................................................................................................................ 23
doelwitgenen HIF1 ..................................................................................................................................................... 24
de vorming van nieuwe bloedvaten d.m.v sprouting ........................................................................ 25
het proces van sprouting .............................................................................................................................. 25
de ‘tip’ cel ...................................................................................................................................................... 26
Kenmerken................................................................................................................................................................. 26
Proces ........................................................................................................................................................................ 26
selectie van ‘tip’ cel.................................................................................................................................................... 26
de ‘stalk’ cel................................................................................................................................................... 27
kenmerken ................................................................................................................................................................. 27
notch signalisatie ....................................................................................................................................................... 27
elongatie van de ‘stalk’ cel ......................................................................................................................................... 27
rol van VEGFR-1 ......................................................................................................................................................... 28
‘Tip’ cel vs. ‘stalk’ cel .................................................................................................................................................. 28
stalk cellen en vorming van een lumen...................................................................................................................... 28
de ‘falanx’ cel ................................................................................................................................................ 28
kenmerken ................................................................................................................................................................. 28
mauturatie van het gevormde bloedvat ....................................................................................................... 29
kenmerken ................................................................................................................................................................. 29
hypoxie veroorzaakt een abnormale tumorvasculatuur ................................................................... 29
proces ........................................................................................................................................................................ 30
antiangiogene middelen in de behandeling van kanker.................................................................... 30
inhibitie van angiogenese via VEGF .............................................................................................................. 30
medicatie....................................................................................................................................................... 30
normalisatie van de tumorvasculatuur.............................................................................................. 31
endotheliale normalisatie bij phd-2 haplodeficiënte muizen ....................................................................... 31
bijkoende mechanismen die leiden tot verhoogde bloedtoevoer .................................................... 32
(2) ‘Intussusceptive’ microvasculaire groei ................................................................................................... 32
(3) Vasculaire co-optie .................................................................................................................................. 33
(4) vasculogenese .......................................................................................................................................... 33
vasculogene ‘mimicry’ ................................................................................................................................... 33
rol van kankerstamcellen in tumor neovascularisatie .................................................................................. 33
les 3: oncogenetica: epigenetische veranderingen........................................... 34
inleiding ............................................................................................................................................. 34
Vroeger.......................................................................................................................................................... 34
3
, NU ................................................................................................................................................................. 34
DNA methylatie.................................................................................................................................. 35
Cpg ................................................................................................................................................................ 35
hoe Cpg eiland vinden? ................................................................................................................................. 35
regulatie methylatiE ...................................................................................................................................... 35
histon modificaties ............................................................................................................................ 36
histonmodificaties ......................................................................................................................................... 36
hat .............................................................................................................................................................................. 37
hdac ........................................................................................................................................................................... 37
interactie epigenetica ................................................................................................................................................ 37
tumor initiatie en epigenetisch landschap ........................................................................................ 38
inactivatie TSG............................................................................................................................................... 38
eigenschappen methylatie ............................................................................................................................ 38
epigenetische landschap in kanker .................................................................................................... 38
algemeen ....................................................................................................................................................... 38
hoeveel? ........................................................................................................................................................ 39
waarom? ....................................................................................................................................................... 39
wanneer? ...................................................................................................................................................... 40
interactie genetica-epigenetica ......................................................................................................... 40
MSI tumoren ................................................................................................................................................. 40
hMLH1 ....................................................................................................................................................................... 41
mgmt (methyltransferase) ............................................................................................................................ 41
wnt signaling pathway .................................................................................................................................. 41
MicroRNAs ......................................................................................................................................... 42
Technieken ......................................................................................................................................... 42
bisulfiet behandeling + Pcr ............................................................................................................................ 42
Pyrosequencing ............................................................................................................................................. 43
array .............................................................................................................................................................. 44
werking ...................................................................................................................................................................... 44
ngs ................................................................................................................................................................. 45
capturing .................................................................................................................................................................... 45
no capture, whole genome ........................................................................................................................................ 46
overzicht ........................................................................................................................................................ 47
les 4: oncogenetica: research ........................................................................... 48
inleiding ............................................................................................................................................. 48
tumorheterogeniteit ..................................................................................................................................... 48
4
1
,Les 1: Doelgerichte therapieën .......................................................................... 8
Inleiding ............................................................................................................................................... 8
Hallmarks of cancer ......................................................................................................................................... 8
Behandeling .................................................................................................................................................... 8
Definities ......................................................................................................................................................... 9
Gefractioneerd toedienen ............................................................................................................................. 10
Doelgerichte kankerbehandeling....................................................................................................... 10
Algemeen: definitie ....................................................................................................................................... 10
Doelgerichte therapie ................................................................................................................................................ 10
Definities .................................................................................................................................................................... 11
Ideale targets ............................................................................................................................................................. 11
Aangrijpingspunten van doelgerichte therapie............................................................................................. 12
Hormonale therapie................................................................................................................................................... 12
Signaaltransductie ..................................................................................................................................................... 13
Monoklonale antilichamen ........................................................................................................................................ 13
Tyrosinekinase inhibitoren......................................................................................................................................... 15
Angiogene therapie ................................................................................................................................................... 15
Uitdagingen van doelgerichte therapie......................................................................................................... 15
Voorbeeld doelgerichte therapie: de EGFR-pathway als aangrijpingspunt....................................... 16
Algemeen: de EGFR pathway ........................................................................................................................ 16
Anti-EGFR therapie ........................................................................................................................................ 17
Tyrosine kinase inhibitoren (TKI) ............................................................................................................................... 17
Monoklonale antilichamen ........................................................................................................................................ 17
Biomerkers ......................................................................................................................................... 18
Types biomerkers .......................................................................................................................................... 18
biomerker voor aanleg............................................................................................................................................... 18
screeningsbiomerker ................................................................................................................................................. 18
diagnostische biomerkers .......................................................................................................................................... 19
prognostische biomerkers ......................................................................................................................................... 19
predictieve biomerkers .............................................................................................................................................. 19
farmacodynamische biomerker ................................................................................................................................. 20
herval biomerker ....................................................................................................................................................... 20
uitdagingen biomerkers ............................................................................................................................................. 20
EGFR en KRAS als biomerker ......................................................................................................................... 20
EGFR ALS BIOMERKER ................................................................................................................................................ 20
KRAS ........................................................................................................................................................................... 21
Les 2: angiogenese ........................................................................................... 22
HIF activeert angiogene factoren ...................................................................................................... 22
2
, algemeen ....................................................................................................................................................... 22
HIF1: hypoxie-induceerbare factor ............................................................................................................... 23
structuur HIF1 ............................................................................................................................................................ 23
Proces HIF1 ................................................................................................................................................................ 23
doelwitgenen HIF1 ..................................................................................................................................................... 24
de vorming van nieuwe bloedvaten d.m.v sprouting ........................................................................ 25
het proces van sprouting .............................................................................................................................. 25
de ‘tip’ cel ...................................................................................................................................................... 26
Kenmerken................................................................................................................................................................. 26
Proces ........................................................................................................................................................................ 26
selectie van ‘tip’ cel.................................................................................................................................................... 26
de ‘stalk’ cel................................................................................................................................................... 27
kenmerken ................................................................................................................................................................. 27
notch signalisatie ....................................................................................................................................................... 27
elongatie van de ‘stalk’ cel ......................................................................................................................................... 27
rol van VEGFR-1 ......................................................................................................................................................... 28
‘Tip’ cel vs. ‘stalk’ cel .................................................................................................................................................. 28
stalk cellen en vorming van een lumen...................................................................................................................... 28
de ‘falanx’ cel ................................................................................................................................................ 28
kenmerken ................................................................................................................................................................. 28
mauturatie van het gevormde bloedvat ....................................................................................................... 29
kenmerken ................................................................................................................................................................. 29
hypoxie veroorzaakt een abnormale tumorvasculatuur ................................................................... 29
proces ........................................................................................................................................................................ 30
antiangiogene middelen in de behandeling van kanker.................................................................... 30
inhibitie van angiogenese via VEGF .............................................................................................................. 30
medicatie....................................................................................................................................................... 30
normalisatie van de tumorvasculatuur.............................................................................................. 31
endotheliale normalisatie bij phd-2 haplodeficiënte muizen ....................................................................... 31
bijkoende mechanismen die leiden tot verhoogde bloedtoevoer .................................................... 32
(2) ‘Intussusceptive’ microvasculaire groei ................................................................................................... 32
(3) Vasculaire co-optie .................................................................................................................................. 33
(4) vasculogenese .......................................................................................................................................... 33
vasculogene ‘mimicry’ ................................................................................................................................... 33
rol van kankerstamcellen in tumor neovascularisatie .................................................................................. 33
les 3: oncogenetica: epigenetische veranderingen........................................... 34
inleiding ............................................................................................................................................. 34
Vroeger.......................................................................................................................................................... 34
3
, NU ................................................................................................................................................................. 34
DNA methylatie.................................................................................................................................. 35
Cpg ................................................................................................................................................................ 35
hoe Cpg eiland vinden? ................................................................................................................................. 35
regulatie methylatiE ...................................................................................................................................... 35
histon modificaties ............................................................................................................................ 36
histonmodificaties ......................................................................................................................................... 36
hat .............................................................................................................................................................................. 37
hdac ........................................................................................................................................................................... 37
interactie epigenetica ................................................................................................................................................ 37
tumor initiatie en epigenetisch landschap ........................................................................................ 38
inactivatie TSG............................................................................................................................................... 38
eigenschappen methylatie ............................................................................................................................ 38
epigenetische landschap in kanker .................................................................................................... 38
algemeen ....................................................................................................................................................... 38
hoeveel? ........................................................................................................................................................ 39
waarom? ....................................................................................................................................................... 39
wanneer? ...................................................................................................................................................... 40
interactie genetica-epigenetica ......................................................................................................... 40
MSI tumoren ................................................................................................................................................. 40
hMLH1 ....................................................................................................................................................................... 41
mgmt (methyltransferase) ............................................................................................................................ 41
wnt signaling pathway .................................................................................................................................. 41
MicroRNAs ......................................................................................................................................... 42
Technieken ......................................................................................................................................... 42
bisulfiet behandeling + Pcr ............................................................................................................................ 42
Pyrosequencing ............................................................................................................................................. 43
array .............................................................................................................................................................. 44
werking ...................................................................................................................................................................... 44
ngs ................................................................................................................................................................. 45
capturing .................................................................................................................................................................... 45
no capture, whole genome ........................................................................................................................................ 46
overzicht ........................................................................................................................................................ 47
les 4: oncogenetica: research ........................................................................... 48
inleiding ............................................................................................................................................. 48
tumorheterogeniteit ..................................................................................................................................... 48
4
