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2/26/17
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Nibs,Nabs,Mibs&MabsHeatherL.Sloan,BS,RN,OCN
PugetSoundOncologyNursesSymposium
March2017
Transient
Angiogenesis
RespectsAn@-growth
Signals
NORMALCELLS
Respects
Boundaries
FixedNumberof
Replica@ons
Appropriate
GrowthSignal
ResponsesAppropriate
Apoptosis
Ac@ve
Replica@on
Checkpoints
Recognizedby
ImmuneSystem
Normal
Metabolism
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IgnoresAn@-growth
Signals
Sustained
Prolifera@on
Invadesand
Metastasizes
EscapesApopto@c
Signals
Sustained
Angiogenesis
Unlimited
Replica@ons
Broken
Replica@on
Checkpoints
Evades
Immune
System
Hyperac@ve
Metabolism
CANCERCELLSCHEMOTHERAPY TARGETEDTHERAPY
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TargetedTherapyvsChemotherapy
TARGETEDTHERAPIES
• Actonspecificmolecular
targetsthatareassociated
withcancer
• Compoundsdeliberately
chosenordesignedto
interactwiththeirtarget
• Cytosta@c-theyblock
tumorcellprolifera@on
CHEMOTHERAPY
• Actsonallrapidlydividing
normalandcancerouscells
• Compoundsiden@fied
becausetheykillcells
• Cytotoxic-theykilltumor
cells
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Chemotherapy
Chemotherapyworksbystoppingorslowingthegrowthofcells
whichgrowanddividequickly.
Chemotherapyisusedto:• TreatCancer:curecancer,lessenthechanceitwillreturn,orstoporslow
itsgrowth.
• PalliaOvecare:Shrinktumorsthatarecausingpainandotherproblems.
• Neoadjuvantchemotherapy:Makeatumorsmallerbeforesurgeryor
radia@ontherapy.
• Adjuvantchemotherapy:DestroycancercellsthatmayremainaXer
treatmentwithsurgeryorradia@ontherapy.
• HelpothertreatmentsworkbeYer.
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TargetedCancerTherapy
Targeteddrugszeroinonsomeofthechangesthatmakecancer
cellsdifferent.Theytargetspecificareasofthecancercellthat
allowthecelltogrowfasterandabnormally.Therearemany
differenttargetsoncancercellsandmanydrugsthathavebeen
developedtoaYackthem.
Ingeneraltargeteddrugsworkto:• Blockorturnoffchemicalsignalsthattellthecancercelltogrowand
divide
• Changeproteinswithinthecancercellssothecellsdie
• Stopmakingnewbloodvesselstofeedthecancercells
• Triggeryourimmunesystemtokillthecancercells
• Carryatoxintothecancercelltokillit,butnotnormalcells
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Ourunderstandingofcellbiologywasatone
Omeassimpleasthis…
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Ourcurrent
knowledgenow
revealsatangled
webofsignalingForcellstofuncOonnormally,
complexcommunicaOon
systemsgovernbasiccellular
funcOons:
• Celldivision(prolifera@on)
• Cellmigra@on
• Responsetoexternals@muli
• Celldeath(apoptosis)
Goalsoftargetedtherapy
• Findpathwayuniqueto
cancer
• Developmechanismto
switchpathway“off”
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Extra-&IntracellularSignaling
EGF • Cellscommunicatewith
eachotherbysecre@ng
signals(ligands)which
canbeproteinsorother
molecules.
• Inordertodetecta
signal(thatis,tobe
atargetcell),aneighbor
cellmusthavethe
rightreceptorforthat
signal.
• Whenasignaling
moleculebindstoits
receptor,italtersthe
shapeorac@vityofthe
receptor,triggeringa
changeinsideofthe
cell.
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TargetedTherapies
Discovery:FromBenchtoBedside
Ø FromtargetdiscoverythroughFDAapproval,developinganew
drugtakesatleast10yearsonaverageandcosts$2.6billion.
Ø PhasesofClinicalTrials
Ø PhaseI–safetyandpharmacologyofacompound.15to30
pa@entsglobally.
Ø PhaseII–[email protected]
pa@entsglobally
Ø PhaseIII–comparetostandardtreatment.From100to
thousandsofpa@ents
Target
iden@fica@on
fromtumor
genomics
Target
valida@on
incell
lines
Lead
compounds
inanimal
models
Proof-of-
conceptin
small
pa@ent
sample
Clinical
trials
PhaseI,II
andIII
Ini@alFDA
approvaland
further
studies
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TypesofTargetedTherapies
Nibs:SmallMoleculeKinaseInhibitors
• AkinaseisanenzymethattransfersaphosphategroupfromATPto
aspecificmolecule(phosphoryla@on)
• Kinasesarecri@calinmetabolism,cellsignaling,proteinregula@on,
cellulartransport,secretoryprocesses,andmanyothercellular
pathways.
• Manydifferentkindsofkinases:Proteinkinases,lipidkinases,
carbohydratekinases,nucleosideplusmanymore
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TypesofTargetedTherapies
Nibs:SmallMoleculeKinaseInhibitors
GREEN–EpidermalGrowthFactor
RED–ATPbindingsite
ErloOnib
ATP
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TypesofTargetedTherapies
Nabs:NanoparOcle,Albumin-bound
• Allowsfornon-toxicdeliveryof
hydrophobictherapeu@c
compounds.
• Exploitsthenaturalproper@es
ofalbumin.Albuminreversibly
bindstoandtransportsawide
rangeofmoleculesfromthe
bloodstreamtocells.
• OncetheNab-drugcombo
entertheinters@@alspace,the
drug“payload”isreleasedfrom
thealbumin.
• Thecytotoxicdrugthendiffuses
intothetumorcellswhereit
inducesapoptosis.
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TypesofTargetedTherapies
Mibs:ProteosomeInhibitors
• Theproteosomeisresponsibleforthediges@onofproteinsinside
thecell
• Ifproteasomefunc@onisblocked,thebuild-upoftheseproteins
triggersapoptosis.
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TypesofTargetedTherapies
mAbs:MonoclonalAnObodies
A. Directsignalinginduceddeathof
cancercells(e.g.hercep@nand
rituximab).
B. Inhibitangiogenesis(e.g.
bevacizumab)
C. Blockinhibitorysignalsthereby
resul@nginastrongeran@-tumorT
cellresponse(e.g.ipilimumaband
nivolumab)
D. Deliverradioisotopes(e.g.131I
tositumomab)
E. Deliverhighlypotenttoxicdrugs
directlytocancercells(trastuzumab
emtansine)
F. Retargetimmunecellstowards
cancercellswithspecialmAbthat
connectsthetwo(e.g.
blinatumomab)
G. CART-cells
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TypesofTargetedTherapies
mAbs:MonoclonalAnObodies
Immune
checkpoint
inhibitorsarea
hotareaof
clinicalresearch.
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TypesofTargetedTherapies
mAbs:MonoclonalAnObodies
AnObody
Origin
Naming
Substem
Examples
Chimeric -xi- Rituximab;
cetuximab;
infliximab
Humanized -zu- Trastuzumab;
bevacizumab;
pembrolizumab
Human -u- Ipilumumab;
nivolumab
Bispecific
(BiTEs)
-o- Blinatumomab
Chimeric
Humanized
QuesOons?
Comments?
THANKYOU!!