brain metastases conferencebrain-mets.com/files/31/presentation_2017/8h30_herrera_rios.pdfbrain...
TRANSCRIPT
New models for studies on metastatic cascades and therapy efficacy in
melanoma brain metastases
Herrera Ríos, Dayana “Vascular Oncology & Metastasis”
Skin Cancer Unit of the Dermatology Department University Hospital Essen, Germany
Folie 2 Titel11.10.17
MelanomaIncidence
• in2008>200.000newcasesworldwide;88.500(49%)ineurope
• calculationfor2025->350.000newcases/yearworldwide
1
2
3
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Brainmetastasesinmelanomapatients
• numberofBMdirectsOSinmelanomapatients
• mediansurvivalofmelanomapatientswithBM~3.8month
• BMincidence10-40%duringlifetimeBUT~75%onpatientsautopsy
Thereisaclearneedforimprovedsystemictherapies!
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Immune checkpoints
Cytokine Growth Factor Rev. 2017, 36:33-38
Ipilimumab
NivolumabInhibitors
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MT/ret:Aspontaneoustumormodelformalignantmelanoma
Nature Reviews Cancer 7, 35-45 (January 2007)
Ø fusion of human ret proto-oncogene to mouse metallothionein (MT)-I promotor
Ø ret overexpression promotes melanin production in the root sheets of hair follicles
Ø activation of MAPK signaling pathway
Ø Induction of melanoma in C57Bl/6
ret
MT/ret
MT- I
• Kalkavan Hetal.,Naturecommun 2017• KleinJCetal.,Naturecommun 2017• Carpinteiro etal.,EMBOMolMed.2015• Baldetal.,Nature2014• Helfrichetal.,PCMR2014• Hansenetal.,JExpMed 2013• Helfrichetal.,JExpMed 2010
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Primary melanoma Lymph node
Tyrosinase/PI
MT/ret:Aspontaneousmelanomamodelforbrainmetastasis
Spleen mets
fl-VCT
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TUMORPROGRESSION
QuantificationoftumorloadbyComputerTomography
Metastaticseedingcorrelateswithtumorload
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• Establishmentofcelllinesfrombrainmets• Analyzingbraincolonization&organhomingafterretransplantation
Generationof“matched”celllines
Brainmetastasis
Skinmelanoma
Metastaticlymphnode
BM-ME5
CM
LN
ü RNASeq profileü Functional analysisü Firstinvivoassays are running
Well-characterizedsyngeneicanimalmodelsforBM
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ME-CM(skinmelanoma)
melaninremovalbyCRISP/Cas9technology
Fluorochromlabeling
Winkler/Berghoff
CMcloneinducesbrainmacrometastasis
7differentclones
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BrainmetcelllineRNAexpressionofEMT
MelanomaB16
Skinmelanoma
Melanomalymphnodes
Melanomabrainmet
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• CM(generatedfromprimarymelanoma)
• BM-ME5(generatedfrombrainmet)
Invivoimagingofbrainpenetrationofmelanomacelllines
Ctrl: PBS
Ctrl: PBS
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Summary
• Generated new cell lines with potential for macro metastases for syngeneic transplantation into immunosuppressed mice
• Cell lines, generated from spontaneous brain mets for studies on tumor cell homing
• Development of treatment strategies that increase cancer immune checkpoint therapy
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Group „Vascular Oncology & Metastasis“
Verena SchmittKarolin WieberStefanie LöffekIsa WestedtMara EilebrechtDirk SchadendorfIris Helfrich
Department of Neurology
Josephine Herz
F. WinklerA. Berghoff
Funding:
Acknowledgements
Dr. Konstanze Wegener Stiftung
G. ReifenbergerJ. Felsberg
G. SchackertM. Kirsch
M. HölzelD. Hinze
M. Kato