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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
combinationofthePARP-inhibitorolaparibandneratinibhaveshownsynergisticeffectsin
BRCA wild-type ovarian cancer cell lines and xenografts (40). Preclinical data have also
suggested a benefit from neratinib in Her2/neu overexpressing endometrial cancer,
specificallyinuterineserouscarcinomas(41).Furthermore,interimdatafromtheongoing
phase II SUMMIT basket trial has shown neratinib to have a clinical benefit rate of
54.5%inpatientswithHer2/Neuoverexpressingmetastaticcervicalcancer(42).
Her2/NeuInhibitors—MonoclonalAntibodies
Trastuzumab(rhuMab4D5,Herceptin)
Trastuzumabisarecombinanthumanizedmonoclonalantibodywhichcomprisesthetwo
antigen-specific sites from the murine MuMab4D5. The remainder of the antibody is a
humanIgG.Trastuzumabisdirectedagainstthejuxtamembranousportionoftheextracellular
domainofHer2/Neu.
Severalmechanismsofactionhavebeensuggestedincluding, (i)the preventionofHer2
dimerizationandactivationofdownstreamsignalingcascades,(ii)increasedendocytosisand
therebyreceptor downregulation (43), (iii) cell cycle arrest by release of p27
kip1
(44), (iv)
inhibitionofthematrixmetalloproteinase–mediatedcleavageandsubsequentsheddingofthe
extracellular receptor domain (45), and (v) immune activation, that is, the recruitment of
immune effector cells responsible for antibody-dependent cellular cytotoxicity (ADCC)
(46–48).
Resistancedevelopsthrough(i)alterationsindownstreamsignalingcascades,suchasPTEN
loss(49),(ii)heterodimerizationwithinsulin-likegrowthfactor-1(IGF-1)receptors(50),and
(iii)so-calledreceptorepitopemasking,whichmaybemediatedbytheheavilyglycosylated
extracellulardomainsofoverexpressedandcrowdedmucins(51).
In1992,phaseItrialsoftrastuzumabinbreastcancerwereinitiated.InalargeGynecologic
OncologyGrouptrial, only 95 of 837 (11.4%)patients with recurrentovariancancer
were found to have tumors with Her2/Neu overexpression. Single-agent trastuzumab
resultedinonecomplete(2.4%)andtwopartial(4.9%)responses.Theauthorsconcluded
thatsingle-agenttrastuzumabinrecurrentovariancancerwasoflimitedvalue(52).
For unselected advanced-stage uterine serous carcinomas, single-agent treatment with
trastuzumab has been considered inactive (53), but for advanced stage uterine serous
carcinomas selected for overexpression of Her2/Neu, the combination of carboplatin,
paclitaxel, and trastuzumab has demonstrated an increased progression-free survival
(54).
Pertuzumab(Perjeta)
Pertuzumab is a newer recombinant IgG1 antibody that binds the extracellular domain
further away from the plasma membrane. Pertuzumab appears to be more efficient in the
stericinhibitionofheterodimerizationthantrastuzumab.
PDGFRInhibitors—MonoclonalAntibodies
Olaratumab(Lartruvo)
OlaratumabisahumanmonoclonalIgG1antibodythatisselectivefor,andhashighaffinity
with,theextracellulardomainoftheplatelet-derivedgrowthfactorreceptor(PDGFR)alpha
subunit.Whilethedetailedmechanismofactionisunclear,olaratumabbindinglikelyresults
inreceptordownregulationandinhibitionofdownstreamsignalingcascades.
Preclinicaldatahaveshownreducedproliferationofcancercells(55,56)andincombination
withdoxorubicin,inhibitionoftumorgrowthinosteosarcomaxenografts(57).AphaseIb/II
study showed that the combination of doxorubicin and olaratumab resulted in improved
overall survival in patients with soft tissue sarcomas, including leiomyosarcomas (58).
However,theseresultscouldnotbereplicatedinaphaseIIItrialandolaratumabwastaken
offthemarket(59).
InhibitorsofAngiogenesis
InhibitorsofangiogenesisarepresentedinTable3.2.
VEGFRInhibitors—SmallMolecules
The existing small molecule inhibitors targeting vascular endothelial growth factor
receptor (VEGFR) are considered multikinase inhibitors; they target a variety of
intracellularkinases.TheirmaintargetsareVEGFRandplatelet-derivedgrowthfactor
receptor (PDGFR), specifically on endothelial cells. The affinity to different receptor
subtypesandthespectrumofothertargetedtyrosinekinasesdeterminethecellulareffectsof
eachsmallmoleculeinhibitor.
Cediranib(AZD-2171,Recentin)
Cediranib is a multikinase ATP-competitive inhibitor of the vascular endothelial growth
factorreceptors1–3(VEGFR-1,-2,-3),andthestemcellfactorreceptorc-KIT.Itprevents
VEGF-inducedangiogenesis,regressionofexistingvesselsandinhibitionoftumorgrowthin
adose-dependentmanner(60).Single-agentcediranibhasdemonstrateda17%responserate
in recurrent ovarian cancer (61). In a randomized phase III trial (ICON6 trial), cediranib
maintenance treatment following standard chemotherapy for recurrent platinum-sensitive
ovariancancersignificantlyincreasedprogression-freesurvival(62)butnotoverallsurvival
(63). In a randomized phase II trial, the combination of cediranib and olaparib
comparedwitholaparibaloneinrecurrentplatinum-sensitiveovariancancershowedan
increased progression-free and overall survival in the BRCA wild-type population
(64,65).
Pazopanib(Votrient)
PazopanibisamultikinaseinhibitorcompetingwithATPforitsbindingatthetyrosine
kinasesite(66).StructurallyrelatedtotheadenineringofATP,pazopanibformshydrogen
bonds with the ATP-binding site. Pazopanib targets angiogenesis by inhibiting vascular
endothelial growth factor receptors (VEGFR-1, -2, -3), and platelet-derived growth
factor receptors α + β (PDGFR-α, -β). The inhibition of these receptor systems on
endothelial cells decreases the activation of pathways involved in endothelial cell
proliferation,vascularpermeabilityandendothelialcellmigration,andaccountsforthe
antiangiogenic and antitumor effects of pazopanib (67). Pazopanib inhibits additional
tyrosinekinasesincludingstemcellfactorreceptor(c-KIT),fibroblastgrowthfactorreceptor
(FGFR-1,-2),interleukin-2receptor-inducibleT-cellkinase(Itk),leukocyte-specificprotein
tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms).
However,itisuncleariftheinhibitionofthosetyrosinekinaseshasclinicalrelevance.
Pazopanib has been used as maintenance therapy after first-line chemotherapy for
ovariancancerwithimprovementofprogression-freesurvivalby5.6months(68).The
combinationwithpaclitaxelforrecurrentovariancancer,however,didnotshowanybenefit
(69).Insmallseriesandcasereports,pazopanibhasshownsomeactivityinuterinesarcomas
(70) and carcinosarcomas (71).Pazopanib has also been used in recurrent cervical cancer
(72).
Table3.2SmallMoleculeInhibitorsofAngiogenesis
Sunitinib(SU11248,Sutent)
Sunitinib inhibits the vascular endothelial growth factor receptors 1–3 (VEGFR-1, -2, -3),
platelet-derived growth factor receptors α + β (PDGFR-α, -β), but also fibroblast growth
factor receptor (FGFR-1), stem cell factor receptor c-KIT, RET (rearranged during
transfection),FMS-relatedtyrosinekinase(FLT-3),andcolony-stimulatingfactor1receptor
(CSF1-R)(73).Inpreclinicalstudies,sunitinibdecreasedtumorvascularizationandshowed
antitumoractivityinvariousxenografttumormodels(74–76).Casereports of sunitinib in
recurrent ovarian clear cell cancer were encouraging (77), but a phase II trial showed
minimalactivityinthissetting(78).Similarresultswereobtainedinrecurrentcervicalcancer
(79). A phase II trial of sunitinib in recurrent endometrial cancer showed an 18%
responserate(80).
Sorafenib(BAY43-9006,Nexavar)
Duringinitialscreening,sorafenibwasidentifiedasaninhibitoroftheRafserine/threonine
kinase isoforms (81). In addition, sorafenib was found to inhibit the vascular endothelial
growthfactorreceptors1–3(VEGFR-1,-2,-3),theplatelet-derivedgrowthfactorreceptorβ
(PDGFR-β),FMS-related tyrosinekinase(Flt-3), stemcell factor receptorc-KIT,andRET
(rearranged during transfection). As a type II inhibitor, sorafenib binds to the inactive
conformationofthekinase.
Sorafenib has been shown to induce apoptosis in several tumor cell lines, although the
mechanismofactionisnotknown.Sorafenibisactiveevenincellswiththec-KITmutation
T670IwhichrendersGISTpatientsresistanttoimatinib(82).
While single-agent sorafenib has shown only modest activity in recurrent ovarian
cancer (83), in a randomized phase II trial, sorafenib in combination with topotecan
significantly improved progression-free survival from 4.4 to 6.7 months compared to
topotecan plus placebo (84). In recurrent endometrial cancer, single-agent sorafenib has
demonstratedonlyminimalactivity(85).
Lenvatinib(Lenvima)
Lenvatinib is a multikinase inhibitor. It inhibits the vascular endothelial growth factor
receptors 1–3 (VEGFR-1, -2, -3), and platelet-derived growth factor α (PDGFR-α), in
addition to the fibroblast growth factor receptors (FGFR-1, -2, -3, -4), stem cell factor
receptor c-KIT and RET (rearranged during transfection). In contrast to other available
tyrosinekinaseinhibitors,lenvatinibisapotentinhibitorofFGFR-1aswell,andlikelyexerts
itsantiangiogeniceffectsviainhibitionofVEGFR-2,-3andFGFR-1(86).Theinhibitionof
VEGFR-2isthoughttobethecauseofhypertension,themainsideeffectoflenvatinib.
Thus far,no specific studies on lenvatinib resistance have been reported, but resistance is
possiblymediatedbyupregulationofotherreceptorsandactivationofalternativepathways
(87).
Antitumoractivityhasbeen associatedwithdecreasedtumorvascularization,andhas
beenshown inmanypreclinicalstudies(88). In recent ongoing studies, the combination
therapies that have included lenvatinib have been successful in patients with recurrent
ovarian and endometrial cancer. In one study, the combination of lenvatinib and weekly
paclitaxelresultedinresponseratesof67%(12of18patients)and60%(3of5patients)for
patientswith recurrent ovarianand endometrial cancer,respectively(89). In another study,
the combination of lenvatinib and pembrolizumab yielded a 39.6% response rate in
patients with advanced stage endometrial cancer (90). The FDA approved the
combination of lenvatinib and pembrolizumab for the treatment of recurrent
endometrialcancerinSeptember2019.
VEGFRInhibitors—MonoclonalAntibodies
Bevacizumab(Avastin)
In 2004, bevacizumab became the first FDA approved angiogenesis inhibitor. It is a
recombinanthumanizedmonoclonalantibodythatbindsspecificallyallisoformsofthe
vascular endothelial growth factor-A (VEGF-A), that is, the ligand, and thereby
preventsbindingoftheligandVEGF-AtothereceptorsVEGFR-1and-2onthesurface
of endothelial cells. VEGFR-2 is thought to be mainly responsible for signaling in
angiogenesis. Bevacizumab is derived from mice that were immunized with a 165-amino
acidresidueofVEGF-A.Exceptforthebindingregion,therestofthemouseantibodywas
replaced by human full light chains and truncated IgG1 heavy chains. The plasmid is
expressedinChinesehamsterovarycells.
Thedevelopmentofbevacizumabwasconnectedtothediscovery,isolation,andcloning
of VEGF at Genentech in 1989. In 1993, Kim and colleagues reported that tumor
angiogenesis and tumor growth could be suppressed using specific antibodies (91).
Bevacizumab inhibits the growth of new vessels, triggers the regression of newly formed
vessels,andresultsinnormalizationofthetumorvasculature.Bevacizumabinhibitsinvitro
VEGF-induced cell growth, permeability, nitric oxide production, and cell migration (92).
Fordiscussionofrelevantclinicaltrialsofbevacizumabforthetreatmentofcervical,ovarian,
andendometrialcancer,seeChapters9,10,and11.
Resistance to antiangiogenics or antiangiogenic treatment is mediated through
alternativeangiogenicescapepathways:
Angiogenic inhibition results in the release of proangiogenic cytokines, including
placentalgrowth factor (PGF), angiopoietin (ANG1), fibroblast growth factors (FGFs),
andstromalcell-derivedfactor1(SDF1)(93).
Proangiogenic cytokines recruit vascular progenitor cells which give rise to new blood
vessels(94),andantiangiogenictreatment leadstobloodvesselsthat showanincreased
pericytecoverageanddecreasedsensitivitytoantiangiogenictherapy(95).
Tumorcellsmaygrowalongexistingbloodvesselsand“co-opt”thosevessels(96).
Cancercellscanform blood vessels even in the absence of endothelial cells; a process
knownasvascularmimicry(97).
Antiangiogenic treatment can induce tumor dormancy, which reduces the efficacy of
chemotherapy(98).
Aberrantreceptorglycosylationpermitsgalectin-1bindingtoVEGFR2receptorswhichin
turnleadstoreceptorclusteringandactivation,evenintheabsenceofVEGFligand(99).
InhibitorsofOtherIntracellularKinases
SmallMolecules
SmallmoleculeinhibitorsofotherintracellularkinasesarepresentedinTable3.3.
Braf(RapidlyActivatedFibrosarcoma)Inhibitors
Vemurafenib(Zelboraf),andDabrafenib(Tafinlar)
VemurafenibinterruptstheBraf/MEKstepintheMAPKsignalingcascade(seeChapter1).
VemurafenibisonlyeffectiveiftheBrafV600Emutationispresentinwhichavaline(V)is
replacedbyglutamicacid(E).ABrafV600EmutationcausesconstitutiveactivationofBraf.
Vemurafenib binds to the ATP-binding domain of the mutated Braf. Sixty percent of
melanomascomprisethisV600Emutation.InmelanomacellslackingtheV600Emutation,
however,vemurafenibhastheoppositeeffectandstimulatescancercellproliferation(100).
KnownresistancemechanismstovemurafenibincludemutationsofNrasthatreactivatethe
raf/rassignaling cascade (101) andhepatocytegrowth factor expression bystroma cells of
thetumormicroenvironment(102).Therehavebeencasereportsandsmallseriesofthe
successful use of vemurafenib in low-grade ovarian cancers that have a Braf V600E
mutation(103,104).
MEK1-2(MAPK/ERKKinase)Inhibitors
Trametinib(Mekinist)
TrametinibisahighlyselectivereversibleallostericinhibitorofMEK1andMEK2activity.It
bindsMEK adjacent tothe ATP-bindingsite and therebyinhibits the dualphosphorylation
required for MEK activation. Case reports are available in the literature describing its use
withandwithoutdabrafenib(seeabove)forthetreatmentoflow-gradeserousovariancancer
withBraf or Nras mutations (105,106).Arandomized phaseII/III trial of trametinib in
low-gradeserousovariancancershowedanincreasedresponserate(26.2%vs.6.2%),
andprogression-freesurvival(13.0vs.7.2months)comparedtostandardofcare(107).
Table3.3SmallMoleculeInhibitorsofOtherIntracellularKinases
CDK4-6(Cyclin-DependentKinases4-6)Inhibitors
Palbociclib(PD0332991,Ibrance)
Palbociclibisaspecificreversibleinhibitorofthecyclin-dependentkinases4and 6(CDK
4-6).ItinterfereswiththeCDK4-6-cyclinD1complex,whichresultsin(i)retinoblastoma
(Rb) hypo-phosphorylation and (ii) prevention of the E2F transcription factor release.
Together,theseresultincell-cyclearrestintheG1phase.Basedoninitialpreclinicalstudies,
itwas thoughtthatfor palbociclib tofunction,a functional cellularRbwould be required,
which could be assessed by measuring the intracellular phosphorylated Rb (108,109).
Subsequentstudieshaveshownthatthelossinexpressionofretinoblastomaproteinresultsin
palbociclib nonresponsiveness, at least in cell line models (110,111). Although primary
resistance to palbociclib and development of resistance during palbociclib treatment are
known issues, the clinical relevance of retinoblastoma expression for palbociclib
responsivenesshas notbeen validated.Other possiblypredictivemarkers arebeing studied
(112). In preclinical studies, palbociclib has induced potent G1 arrest in cell lines and
xenografts (113,114). Clinical data thus far are sparse; trials of combination therapy with
CDK4-6inhibitorsarecurrentlyongoing.
Ribociclib(Kisqali)
Ribociclibhasasimilarmechanismofactionandefficacytopalbociclib.Itssideeffectsare
also similar, except that QT prolongation is more frequent with ribociclib (115).
CombinationtreatmentofribociclibandletrozolehasbeenreportedinaphaseIItrialof
recurrent estrogen-receptor (ER)–positive ovarian and endometrial cancers. The 12monthprogression-freesurvivalwas50%forovarianand55%forendometrialcancer,
respectively(116).
ALK(AnaplasticLymphomaKinase)Inhibitors
Crizotinib(Xalkori)
Crizotinibwasoriginallydevelopedtoinhibitthemesenchymal epithelialtransitiongrowth
factor(c-Met),butitisalsoapotentinhibitoroftheanaplasticlymphomakinase(ALK)and
oftherelatedROS1kinase.ItbindswithintheATP-bindingpocketofthesetyrosinekinases.
Resistancesinferredbyaminoacidsubstitutionsthathinderstericallydrugbindinghavebeen
described,forexample,L1196MandL1152RinALK.Onlypreclinicaldataoncrizotinibin
combinationwithcisplatininovariancancermodelsexist(117).
PI-3K(Phosphatidylinositol3-Kinase)Inhibitors
Thegroup ofsmall moleculePI-3K inhibitorsincludes (i)pan-classI PI-3Kinhibitors, (ii)
isoformselectiveclassIPI-3Kinhibitors,and(iii)dualPI-3K/mTORinhibitors.Pan-classI
PI-3Kinhibitorstargetallisoformsδofthecatalyticsubunitp110,thatis,p110α,β,γandδ.
The isoform δ-specific idelalisib (Zydelig) was the first PI-3K inhibitor that was FDA
approved for different leukemias in 2014. PI-3K inhibitors for gynecologic malignancies
have been thus far experimental. In the following, we will only discuss a few examples
whichhavebeendescribedinpublishedclinicaltrials.
Buparlisib(BKM120)
Buparlisib is an oral reversible pan-class I PI-3K inhibitor. It has shown antiproliferative
activityincancercelllineswithPI-3KalterationsandhasdecreasedtumorsizeinPIK3CA
(phosphatidylinositol 3-kinase, catalytic subunit α)-mutant xenografts (118). In the first
phaseItrial,buparlisibwasshowntobewelltoleratedandtohaveactivity,buttheroleof
the molecular status of PIK3C or PTEN (phosphatase and tensin homolog) in predicting
outcomeremainedunclear(119).
CombinationtreatmentwithtrametinibforrecurrentKras-mutantovariancancerhas
demonstratedpromisingantitumoractivity(120).InanotherphaseItrial,thecombination
witholaparib displayed antitumor activity in patients with recurrent ovarian cancer (121).
However,inaphaseIItrial,buparlisibassingle-agentinrecurrentendometrialcancerhada
poorsafetyprofileandonlyminimalactivity(122).
Apitolisib(RG7422,GDC-0980)
Apitolisibisanoraldualinhibitorofpan-classIPI-3KandmTOR1-2(mammaliantargetof
rapamycin).Inseveralpreclinicalstudies,apitolisibhasshown antitumoractivity(123). A
phase I study using single-agent apitolisib for recurrent or progressive endometrial cancer
revealedantitumoractivitywitha dailydose limitedby tolerability,especiallyindiabetics.
The three patients with confirmed responses displayed alterations in the PI-3K pathway
(124).
Gedatolisib(PF-05212384,PKI-587)
Gedatolisib is an intravenous ATP-competitive dual pan-class I PI-3K and mTOR1-2
inhibitor with antitumor activity in preclinical studies (125). Weekly infusions of single-
agentgedatolisibinpatientswithrecurrentendometrialcancerhaveshowna53%(10
outof19)clinicalbenefitrateandacceptabletolerability(126).
Copanlisib(BAY80-6946)
Copanlisib is an intravenous pan-class I PI-3K inhibitor with preferential activity against
p110αandβisoforms.Ithasdemonstratedantitumoractivityinpreclinicalmodels(127).In
aphaseItrialofsingle-agentcopanlisibinfour patientswithrecurrent endometrialcancer,
one patient had a complete response, two had stable disease, and one had disease
progression.Inthecompleteresponder,bothPIK3CandPTENweremutated(128).
mTOR(MammalianTargetofRapamycin)Inhibitors
Rapamycin,Sirolimus(Rapamune)
Rapamycinorsirolimusisanaturalproductfromthe bacteriaStreptomyceshygroscopicus,
foundonRapaNuiin1972(129).Itisstructurallyrelatedtothemacrolidelactoneantibiotic