Targeted therapy: van ‘proof of concept’ naar ‘personalised cancer care’ Carla van Herpen Internist-oncoloog 14 mei 2013
Intracellular signaling networks regulate the operations of the cancer cell
Hanahan and Weinberg Cell 2011;144:646
GIST (GastroIntestinal Stroma cell Tumor)
• Ca 250-300 NP per jaar in Nederland • Meestal bij ouderen (50 jaar en ouder..)
• Zelden familiair • Wel vaak (20%; eigen data) tweede tumoren
• Onderdeel van M Recklinghausen (met meestal wild type)
Histopathology of GIST: Biological Markers Used in Diagnosis of GIST
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GISTs positive for CD117 (c-Kit receptor tyrosine kinase) Positive in >95% − CD34 (mesenchymal/haematopoietic precursor cell marker) Positive in 60% to 70% − Vimentin and smooth muscle actin Positive in 15% to 60% DOG: positive GISTs do not express Desmin S-100
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CD117 (c-Kit)–positive staining GIST
Imatinib eerste echte doelgerichte therapie in de oncologie A selective tyrosine kinase inhibitor of: Bcr-Abl PDGF-R c-Kit
First used in Philadelphia chromosome–positive (Ph+) CML Target Bcr-Abl
Mediane overleving GIST : van 9 maanden naar 5 jaar!
KIT and PDGFRA Mutaties in GIST KIT
PDGFRA
Overall mutation frequency: 87.4%
Exon 9 (11%) Membrane Exon 11 (67.5%) Exon 13 (0.9%)
Exon 12 (0.9%) Exon 14 (0.3%)
Exon 17 (0.5%)
Cytoplasm Exon 18 (6.3%) Heinrich Hum Pathol. 2002;33:484. Corless Proc Am Assoc Cancer Res. 2003;44.
Imatinib-resistant GIST - relevance of exon 9 mutation -
Wat heeft GIST ons gebracht?
• Inzicht in totaal nieuwe therapie • Andere bijwerkingen • Resistentie • First line, second line, third line • Dose finding • Relatie dose-respons • Relatie mutatie –response • Nieuw methoden van evaluatie • Hoe om te gaan als oncologische gemeenschap met een zeldzame tumor!
Antikanker middelen geregistreerd door de FDA tussen aug 2011 en dec 2012
(13/17 targeted agents) Awada Current Opninion 2013;25:296
Personalised cancer care “ …the tailoring of medical treatment to the individual characteristics of each patient; to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment so that preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not.” “ …the molecular methods that make personalized medicine possible include testing for variations in genes, gene expression, proteins, and metabolites, as well as new treatments that target molecular mechanisms. Test results are correlated with clinical factors to help physicians individualize treatment for each patient” US Presidents’ Council of Advisors on Science and tecnology Personalized Medicine Coalition
Therapeutic targeting of the Hallmarks of Cancer
Hanahan and Weinberg Cell 2011;144:646
Melanoom
Vemurafenib: BRAF inhibitor Selective for BRAFV600E kinase among 70 kinases screened BRA F
IC50 (nM) 10–100 100–1000 1000–10000
Sosman; NEJM 2012;366:707
Treatment with Vemurafenib With BRAF mutation …..TACAGTGAAA….. …..TACAGAGAAA…..
Without BRAF mutation …..TACAGTGAAA…..
PARP inhibitie in ovarium ca
• Poly ADP Ribose Polymerase • Familie van 17 of verwante eiwitten (PARP 1-16), waarvan parp 1 en 2 het meest bekend zijn • Bevindt zich in de celkern • Meest bekend is PARP 1
Werkingsmechanisme PARP
• Ontdekt enkelstrengs breuken in het DNA
PARP (poly ADP-ribose polymerase)
PARP inhibitie: BRCA1 en BRCA2 mutaties: extra gevoelig BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. Farmer Nature 2005;434:917 Bryant Nature 2005;434:913
Olaparib (PARP-I) maintenance therapy in platinum-sensitive relapsed high grade serous ovarian cancer
Ledermann NEJM 2012;366:1382
Challenges/uitdagingen
• Biopteren • Resistentie • Tumor response assessment • Tumor heterogeniteit • Combinaties van targeted agents • Kosten
Biopteren
• Natuurlijk voor diagnose en eerste metastase • Maar ook later in ziekte beloop: •
− discordantie bv in mammaca PT en metastasen: ER 16%, PR 40% en HER2 10% − Mammaca HER-2+: 24% HER-2- metastasen Om response/resistentie te onderzoeken: ontwikkelen van prognostische en predictieve biomarkers (research biopten: ethisch?) − In fase I – vroeg fase II trials: biopten: 1.4% ernstige complicaties
Resistentie
• Treedt bijna altijd op • Soms niet (6 jr CR BRAF gemut melanoom in fase I met AZD6244 behandeld) • Biopten
Boers-Sonderen Anticancer Drugs. 2012;23:761
Synoviasarcoom fase I ifosfamide-pazopanib 19-4-2011 baseline
13-3-2012 PR
9-10-2012 PR, echter groei 1 lesie: operatie, door met pazopanib; Mutatie analyse volgt
IH Staining of progressive lesion at time of PD of a patient who initially responded to vemurafenib but then progressed
Trunzer JCO 2013;31:1767
Tumor response assessment Therapy with signal transduction modifiers: role model : imatinib treatment of GIST
imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-kit mutation Kit receptor signaling regulates glucose uptake as well as glucose metabolism (strong decrease of hexokinase and glucose-6-phosphate 1-dehydrogenase activity) FDG-PET
FDG-PET in GIST during sunitinib (2 wks on / 2 wks off) baseline
cycle 1, d7
cycle 1, d28
cycle 2, d14
Demetri et al. CCR 2009;15:5902-5909
Tumor heterogeniteit in niercel carcinoom 63 to 69% of all somatic mutations not detectable across every tumor region Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. 26 of 30 tumor samples from four tumors harboring divergent allelicimbalance profiles and with ploidy heterogeneity in two of four tumors
Gerlinger NEJM 2012;366:883
Combinatie therapieën: is meer altijd beter?
• Combinaties soms te toxisch • In HER-2+ gemetastaseerd mammaca: − Pertuzumab en trastuzumab met docetaxel: PFS 18.5 mnd vs 12.5 mnd met trastuzumab en docetaxel − Kosten $ 188.000
• BRAF remmer met PI3KI met EGFR-Ab in BRAF gemuteerd gemetastaseerd CRC: fase I
Kosten
• Meeste orale middelen:
€3600 en 5500 per maand
• Combi: Pertuzumab en trastuzumab met docetaxel: $ 188.000 voor 1.5 jaar
Samenwerking met de moleculaire pathologie
• Snelheid
− soms snelle groei tumoren
− Om patiënten te kunnen includeren in studies
• Gevalideerde testen • Snel schakelen − Na ASCO of AACR: wellicht nieuwe targets Samen met de klinische farmacie, pathologie, nucleaire geneeskunde, radiologie, tumorimmunologie
