Nibs, Nabs, Mibs & Mabs NORMAL CELLSpsons.org/wp-content/uploads/2017/02/HSloan-Nibs-Nabs-Mibs-Mabs.pdfNibs, Nabs, Mibs & Mabs Heather L. Sloan, BS, RN, OCN Puget Sound Oncology Nurses

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?

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