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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
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3
Biologic,Targeted,andImmune
Therapy
MalteRenz
JonathanS.Berek
OliverDorigo
Intheearly1900s,PaulEhrlichpostulatedamagicbullet(“Zauberkugel”)forthetreatment
of diseases in general, and cancer and parasitic diseases in particular.Since diseased cells
could be stained to differentiate them from normal cells—so went Ehrlich’s rationale—it
shouldbepossibletotargetdiseasedcellsspecifically.Accordingly,Ehrlichtriedtodevelop
drugstargetingtrypanosomes(1).Ehrlich’sconsiderationsandtherapeuticattemptscouldbe
consideredanearlypostulatefortargetedtherapies.
Targetedtherapiesareaimedatsignalingmoleculesthataremoreactiveincancercells
thaninnormalcells.Thesemoleculesarecriticalforcancercellgrowthandmetastasis.
Bytargetingdifferentiallyexpressedandactivemoleculesandeliminatingtheiractivity,
targetedtherapiesaffectcancercellsmorethannormalcells.
The definitions of the terms, biologics, targeted therapy, and immune therapy are
variable based on the published literature, and there is some overlap between the three
therapeuticstrategies.Target molecules may be molecules criticalforproliferation and
invasionofcancercells.Targetmoleculesmayalsobemoleculesintheimmunesystem
which help eliminate cancer cells. In this sense, immune therapy is a subcategory of
targetedtherapies.However,toolsofimmunetherapy,thatis,antibodies,canbeusedto
targetsignalingmoleculesindependentofenhancingtheimmunesystem.Therecently
expanding field of immunotherapy now includes targeted cell therapies and cancer
vaccinations and has progressively developed as an independent field of its own. All
pharmacologicmeansoftargetedtherapies,thatis,smallmoleculesandantibodies,can
beconsideredbiologics.
Twoclassesof targeted therapies can bedefined,(i)small molecule kinase inhibitors,
thatcanenterthecellbydiffusionthroughtheplasmamembrane,and(ii)antibodies,
largeproteinsthatcannotenterthecell,andbindtosurfaceproteinsandmaythenbe
takenupbyendocytosis.
Theclassofsmallmoleculekinaseinhibitorshasbeen growingconsiderably inthe last10
years.Smallmoleculekinaseinhibitorscanbeclassifiedaccordingtotheirbiochemical
mechanism of action. Dar and Shokat (2) proposed a classification comprising three
types.TypeIis a“small moleculethatbindstotheactiveconformationofakinaseinthe
ATP pocket.” This type includes most of described inhibitors, for example, crizotinib and
pazopanib.TypeII smallmoleculesbindto an inactive conformation of a kinase, such as
sorafenib.TypeIIIisanallostericnon-ATPcompetitiveinhibitorthatbindstoasitenextto
the ATP-binding pocket, for example, trametinib. Various extensions of this basic
classificationhavebeensuggested(3,4).
Forantibodies,theWHOnomenclaturemayprovideaclassification.Thestem“-mab”
indicatesmonoclonalantibodies. The substem for the animal origin of the antibody was
droppedin2017butisstillpartofolderantibodynames (-o-formouse,-a-forrat,-e-for
hamster, -i- for primates). For humanized antibodies, -zu- follows or -xi- for chimeric
antibodies(onlyFcregionreplaced).Thesubsetprecedingthesourceoftheantibodydefines
its target. Examples are -ci(r)- for circulatory system, -li(m) for immune system. The old
systemuseddifferenttumordesignations,forexample,-go(v)forovariancancer,whilethe
new system only employs the site agnostic -t(u). The leading first 1–2 syllables in an
antibody name are without any meaning. Withthisclassificationin mind, antibody names
canbedissected as exemplified with the anti–VEGF-A antibody beva-ci-zu-mab:it targets
thecirculatorysystem(-ci-),andisahumanized(-zu-)monoclonalantibody(-mab).
In this chapter, we present a synopsis of targeted therapies, including immune therapy
relevantfor gynecologicmalignancies,focusing mainlyon the biologyand mechanisms of
these therapies. We focus only on preclinical and clinical data of those therapies in
gynecologicmalignanciesunlessdescribedelsewhereinthisbook,asnoted.
InhibitorsofGrowthFactorReceptors
InhibitorsofgrowthfactorreceptorsarepresentedinTable3.1.
EGFRInhibitors
Theepidermalgrowthfactorreceptor(EGFR)belongstotheerbB/Herreceptorfamily
(see Chapter 1). Targeted therapies exist and are in clinical use for two of the four
receptorsofthisfamily,thatis,EGFR(erbB1orHer1)andHer2/Neu.
EGFRInhibitors—SmallMolecules
Gefitinib(ZD1839,Iressa)
GefitinibwasthefirstselectiveEGFRtyrosinekinaseinhibitordescribed.Itbindstothe
ATP-binding pocket of the intracellular EGFR tyrosine kinase domain and prevents ATP
binding and thereby transphosphorylation of the activated EGFR dimers. Gefitinib has
demonstratedonlylimitedclinicalbenefitingynecologicmalignancies.InaGynecologic
Oncology Group (GOG) trial, 27 patients with recurrent or persistent ovarian cancer were
treatedwithdailygefitinib.Four of27patients(14.8%)survived progression-freeformore
than6months,withoneobjectiveresponse(3.6%).EGFRoverexpressionwasassociated
withlongerprogression-freesurvivalandpossiblylongersurvival. Thepatient withthe
only objective antitumor response had a mutation in the catalytic domain of the tumor’s
EGFR(2235del15)(5).Inadifferenttrial,forthe16patientswhocompletedmorethantwo
cyclesofdailygefitinib,nocompleteorpartialresponseswereobserved.However,gefitinib
inhibitedphosphorylationofEGFR,therebyprovidingaconceptualproofoftargetedtherapy
(6).
Table3.1InhibitorsofGrowthFactorReceptors
Gefitinibhasalsobeenstudiedincombinationwithstandardchemotherapyinpatients
with ovarian cancer. Combined with carboplatin and paclitaxel, gefitinib resulted in an
overall response rate of 63% in recurrent ovarian cancer. Response rates were 35% in
platinum-resistantdiseaseand73%inplatinum-sensitivedisease.Noneofthe18treated
patientsshowedEGFRreceptormutations(7).Gefitinib in combinationwithtamoxifen for
recurrentplatinum-resistantovariancancerhasnotresultedinobjectiveantitumorresponses,
but16patientsshowedstabledisease(8).Inrecurrentsquamouscellandadenocarcinomaof
thecervix,gefitinib treatment yielded stable disease in 6 out of 28 patients (20%) but no
clinicalresponses(9).
Erlotinib(Tarceva)
Likegefitinib,erlotinibisatyrosinekinaseinhibitorthatspecificallytargetsEGFR.The
main differences between the two tyrosine kinase inhibitors seem to be related to their
pharmacokinetics. Resistance mechanisms to both small molecule EGFR kinase inhibitors
are likely to be similar. Substitution of a threonine by the nonpolar larger methionine
(T790M)withintheATP-bindingpocketresultsinresistancebyeither(i)sterichindranceof
thebulky methionine preventingaccess of theEGFR tyrosine kinaseinhibitorto theATPbindingpocket(gatekeepermutation)(10),or(ii)increasedATP-bindingaffinityandthereby
reduced small molecule binding (11). While mutations in the ATP-binding pocket are the
most frequent form of resistance, other mechanisms have been described for erlotinib and
gefitinibincluding(i)mutationofthehepatocytegrowthfactorthatactivatesthroughErbB3
downstream signaling cascades (12,13), (ii) heterodimerization of EGFR with the mutated
insulin-likegrowthfactor-1receptor(IGF-1receptor)allowingtransphosphorylationevenin
thepresenceofEGFRtyrosinekinaseinhibitors(14),and(iii) inactivationof mutations of
thetumorsuppressorgenePTEN(15).
Erlotinib has been used for the treatment of ovarian cancer, but like gefitinib, the
clinicalefficacyhasbeenlimited.Inearlystudies,erlotinibshowedactivityand waswell
tolerated (16). In a phase II trial, erlotinib was added to adjuvant chemotherapy with six
cycles of carboplatin and paclitaxel after upfront surgery; 29% of the patients received
erlotinibmaintenancetherapy.Thepathologiccompleteresponseatsecond-looksurgerywas
29% and 13% in patients with optimally and suboptimally debulked disease, respectively.
This was similar to historic data without erlotinib, and EGFR amplification was not
correlated with response. The median progression-free survivals were 50.5 and 34.3
months, respectively (17). Erlotinib maintenance treatment after adjuvant chemotherapy
wasalsoshowntooffernosignificantbenefitinaphaseIIItrial.Progression-freesurvivals
forerlotinibversusobservationwere12.7and12.4months,respectively(18).
EGFRInhibitors—MonoclonalAntibodies
Cetuximab(C225,Erbitux)
Cetuximabwasfirstdescribedintheearly1980sasachimericmouse–humanmonoclonal
IgG1 antibody that bound to the extracellular ligand–binding domain of EGFR and
functioned as a competitive antagonist. The binding of cetuximab to EGFR resulted in
internalization of the receptor and thereby receptor downregulation from the cell surface,
which in turn led to inhibition of cell proliferation in cell culture and xenografts (19–21).
Several molecular mechanisms of action have been described including (i) G1 cell cycle
arrest,mediated by increased levelsofthe CDK2 inhibitor p27
kip1
,resultinginRb protein
hypophosphorylation, (ii) induction of apoptosis by activation of Bax and caspase-8, (iii)
decreasedangiogenesisbyinhibitionofEGFR-inducedVEGFandIL8production,and(iv)
decreasedinvasiveness,byreducedproductionofmatrixmetalloproteinase-9(MMP-9)(22).
Mutationsin K-ras (23,24), N-ras, or B-raf (25) are considerednegativepredictorsfor the
responseto EGFR antibodiescetuximab andpanitumumab (see below).Mutations in these
signalingmoleculesdownstreamofEGFRactivatereceptor-independentpathways,andthus
rendercancercellsunresponsivetoanti-EGFRtreatment.EGFRantibodieshave beenused
mainly in metastatic colorectal cancer. Treatment of patients with primary ovarian or
peritonealcancerusingcetuximabhasshownonlymodestactivityinscreenedpatients
withEGFR-positivetumors.Cetuximabincombinationwithcarboplatinresultedinthree
complete(10.7%)andsixpartial(21.4%)responsesamong28patientswithrecurrentovarian
cancer (26). Twenty-six of these 28 patients (92.8%) had EGFR-positive tumors. The
combinationofcarboplatin,paclitaxel,andcetuximabasfirst-linetherapyforpatientswith
stageIIIovariancancerresultedinaprogression-freesurvivalof14.4months,andtherefore
wasnotsignificantlyprolongedcomparedtohistoricaldata(27).
Panitumumab(Vectibix)
Panitumumab is a fully human monoclonal EGFR IgG2 antibody. Like cetuximab,
panitumumab binds to the extracellular domain of EGFR, but it may have different
mechanisms of action. Unlike IgG1 antibodies, IgG2 does not activate the complement
pathwayandantibody-dependentcellularcytotoxicity(ADCC).
Her2/NeuInhibitors
Her2/NeuInhibitors—SmallMolecules
Thusfar,onlydualorpan-Hertyrosinekinaseinhibitorshavebeendescribedandare
inclinicaluse(seeFig.3.1).
Lapatinib(GW2016,TykerborTyverb)
Lapatinib is a dual reversible inhibitor of EGFR and Her2/Neu. Lapatinib binds
noncovalentlytothecysteineresidue(Cys805)intheATP-bindingpocketofthesereceptors.
Lapatinib has a high affinityfor EGFR and Her2/Neu, but is a reversible inhibitor,which
resultsinincompleteinactivationandreactivationofitstargets(28).In2001,theactivityof
lapatinibwasdescribedinpreclinicalmodels(29).Lapatinibinducesaccumulationof Her2
on the cell surface, which may allow for greater trastuzumab-induced antibody-dependent
cell-mediatedcytotoxicity(ADCC)(30). Incontrasttoothertyrosinekinaseinhibitorssuch
as gefitinib and erlotinib, lapatinib and neratinib (see below) interfere with receptor
dimerization. The reversible binding of lapatinib (not neratinib) may result in aberrant
Her2/Her3dimerization,whichmakesthereceptorpronetoactivationbyneuregulin(31,32).
Figure 3.1 Inhibitors of EGFR and Her2/Neu signaling. Inhibiting pharmaceutical agents
areindicatedinredattheirmainsiteofaction.Abbreviationsareasfollows:GF,growthfactor;
EGFR, epidermal growth factor receptor; RAS, rat sarcoma; GTP, guanosine triphosphate;
RAF, rapidly activated fibrosarcoma; MEK 1-2, MAPK/ERK kinase; ERK 1-2, extracellular
signal-regulated kinase; VEGF A, vascular endothelial growth factor A; VEGFR, vascular
endothelial growth factor receptor; PI3K, phosphatidylinositol 3-kinase; PIP2,
phosphatidylinositol 4,5-bisphoshate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PTEN,
phosphataseandtensinhomolog;AKTkinase;TSC1-2,tuberoussclerosisprotein1-2;AMPK,
adenosine monophosphate-activated protein kinase; LKB1, liver kinase B1; Rheb, ras
homologenriched inbrain;mTORC1,mammaliantargetofrapamycin complex 1; mTORC2,
mammaliantarget ofrapamycincomplex2. For furtherexplanation of the depicted signaling
cascades,pleaseseeChapter1.
Single-agent lapatinib in recurrent ovarian cancer has failed to show any objective
responses in 25 patients (33). Lapatinib increased the in vitro efficacy of topotecan (34),
howeveraphaseIItrialinrecurrentovariancancershowedpartialresponseinonly14%of
patients(35). Preclinical studies showed efficacy of lapatinib in Her2/Neu overexpressing
endometrialcancercelllines(36),butaphaseIItrial,GOG229D,demonstratedonlylimited
activityinunselectedpatientswithrecurrentendometrialcancer(37).
Neratinib(Nerlynx)
Neratinib is an irreversible pan-inhibitor of EGFR, Her2/Neu, and Her4. It binds
covalently to cysteine residue Cys805 in the ATP-binding pocket of these receptors.
Compared to lapatinib, neratinib shows affinity also to other kinases downstream of Her
family,includingMEK1-2,whichpotentiallyaddsantiproliferativeeffectsandmayexplain
thehigherpotencyofneratinibcomparedtolapatinib(38).Preclinicaldatahavesuggested
efficacyofneratinibinpatientswithHer2/Neuoverexpressingovariancancer(39).The