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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
FK506 (130). It has multiple properties, including antibacterial, antifungal,
immunosuppressiveandantitumoractivity.ThelatterwasdeterminedduringanNCIscreen
intheearly1980s(131).
Everolimus(Afinitor)
Everolimus is a rapamycin analog, a rapalog, and binds to the protein receptor FKBP-12
(FK506-binding protein). This in turn directly interacts with mTORC1, thus inhibiting
mTORC1downstreamsignaling,whichresultsinG1-Scellcyclearrest.Everolimushaslittle
impact on mTORC2. mTORC1 controls translation, suppresses autophagy, and regulates
transcription and response to DNA damage. mTOR complexes are activated by growth
factors,andinaddition,mTORC1isregulatedbytheintracellularenvironment,thatis,O2-
status,aminoacids,glucose,andenergycharge.InhibitionofmTORC1resultsininhibition
ofTlymphocyteactivationandproliferation,whichareassociatedwithantigenandcytokine
stimulation and the inhibition of antibody production. It has been used to prevent cellular
rejectionafterorgantransplantation.
The antitumor activity of rapamycin has been noted in multiple cancer cell lines and
xenograftmodels.Everolimus has been combined with the aromatase inhibitor letrozolein
recurrent estrogen-receptor positive high-grade ovarian cancer (132). More promising
resultshavebeenseenforthecombinationofletrozoleandeverolimusinpatientswith
recurrentendometrialcancer,whereithasbeenreportedtobeactivein24%ofpatients
(133,134).
Resistance mechanisms have been identified and include point mutations in mTOR that
prevent binding of the rapalog/FKBP-12 complex (135). Long-term exposure to rapalogs
may result in differential gene expression and thereby in drug resistance (136). Specific
miRNAs may also be involved in resistance development (137). Some tumors appear
intrinsically resistant to rapalogs, but the resistance mechanism is unknown. Selective
inhibition of mTORC1 can result in hyperactivation of AKT, since the negative feedback
frommTORC1is inhibited while the positive feedback from mTORC2isstillintact.This
mayresultinlongercellsurvivalinsomecelltypes.
Temsirolimus(Torisel)
Temsirolimusisaprodrug,thatis,itshowsactivityonitsownbutisknowntobeconverted
invivo to sirolimus(rapamycin), which in turn exerts the main activity. This may explain
whysomestudieshavefoundeverolimustobemoreactivein somecancers(138,139), but
alsoassociatedwithmoresideeffects,especiallyrespiratorydisorders(140).
InhibitorsofDNARepair
PARP(Poly-ADPRibose-Polymerase)Inhibitors
The aforementioned targeted therapies have been aimed at protein kinases that are
overexpressedand/oroveractiveandacceleratetumorgrowthandprogression.The concept
ofPARPinhibitionistoexploitadeficiencyofcertaincancerstorepairDNAdamage,while
normalcellsharborrelevantintactDNArepair systems(141).In2005,twogroupsshowed
thattheinhibitionofanonessentialDNArepairsystemcouldbeusedtokillcancercells
that lack homologous recombination (HR), a DNA double-strand repair mechanism
(142,143).The inhibitionofPARP resultsinsingle-strand breaksthat degenerate into
double-strand breaks and eventually result in the collapse of DNA replication.
Unrepaireddouble-strandbreaksinHR-deficientcellsleadtocelldeath.HR-deficient
cells include BRCA-mutated cells and cells with deficiencies in other genes that are
involvedinthecomplexhomologousrecombinationmechanism(144)(seeChapter1).
PARPinhibitioninHR-deficientcancercellsisconsistentwiththeconceptofsynthetic
lethality.Thisconceptpostulatesthattwoindependentandcomplementarygenetichits
thataretoleratedindividuallywillresultincelldeathiftheyoccurtogether (145,146)
(seeChapter1).
All PARP inhibitors, olaparib, niraparib, rucaparib (approved for ovarian cancer),
talazoparib(approvedonlyforbreastcancer),andveliparib(orphandrugfornon–small-cell
lungcancer)effectivelyinhibitpoly[ADP-ribose]polymerase1and2(PARP1-2)although
withdifferentbindingaffinities.
PARPsareADP-ribosylatingenzymesthatbecomeactivatedbybindingtoDNAsingleand double-strand breaks. Auto-ribosylation is necessary to assemble a multiprotein
complexforDNArepair(147–149).PARPenzymesalsoplayaroleinDNAtranscriptionby
acting on chromatin remodeling complexes (150,151) and binding to promotor elements
(152). However, PARP-inhibitors differ in an additional drug effect, that is, the ability to
causePARPtrapping.UndernormalconditionswhenDNAisdamagedintheabsenceof
PARP-inhibitors, PARP enzymes bind to the site of DNA damage and catalyze the
synthesisofADP-ribosepolymers(PAR)thatrecruitDNArepairproteins(Fig.3.2).
Figure3.2PARP-inhibitormechanism. After DNAdamage,the enzymes poly-ADP ribose-
polymerase1and2(PARP1-2)bindtothedamagedDNAandPARylate chromatinproteins
andthemselves.Thereby,DNArepairproteinsarerecruited.ContinuedautoPARylationresults
indestabilizationofthePARP/DNAcomplexandeventuallythedissociationofPARPfromthe
DNA.ThisprocessallowstheDNArepairproteins,baseexcisionrepair(BER),andnucleotide
excisionrepair(NER),tobindtotheDNAdamagesite.UsingPARP-inhibitors(PARP-i),PARP
enzymescannotPARylateand autoPARylate; thus, the PARPenzymesremainboundtothe
siteof DNAdamage and are trapped (PARP trapping). Because ofPARP trapping, theDNA
repair proteins cannot bind. Therefore, the unrepaired single-strand breaks may degenerate
intodouble-strandbreakswhichinturnmaynotbeabletobe repairedin the absence of an
intacthomologousrecombination(HR)repairandmayresultincelldeath.
AutoPARylationof PARP1 induces electrostatic destabilization and dissociation from
theDNAdamagesitewhichpermitsrepairproteinstolocalizetotheDNAdamagesite
(153,154).InPARPtrapping,autoPARylationisinhibited,PARP1andPARP2become
trappedinDNAdamagesitesandblockrecruitmentofDNArepairproteinstotheDNA
damagesite,eventuallyleadingtocelldeath(154).IncreasedPARPtrappingisassociated
with myelosuppression, and may explain the differences in toxicity and doses of different
PARPinhibitors(155).
Table3.4SmallMoleculeInhibitorsofDNARepair
SeveralPARP-inhibitorresistancemechanismshavebeendescribed:
SecondaryreversionmutationswhichrestoretheBRCAopenreadingframeandfunction
arecurrentlythemostacceptedmechanismsofPARP-inhibitorresistance(156,157).
ThereversalofBRCApromotormethylation,thatis,reversalofBRCAsilencing,hasbeen
reported(158).
Hyperactivationofanalternativeerrorpronedouble-strandDNArepairmechanism.This
includestheactivationofnonhomologousendjoining(NHEJ)repairwhichcompensates
fortheHR-deficiency(159).
Loss in 53BP1 (p53-binding protein) function may contribute to PARP-inhibitor
resistance. Under physiologic conditions, 53BP1 promotes NHEJ repair by inhibiting
extensiveDNAend-resectionsthatarerequiredforHRrepair.ItslossinBRCA1-nullcells
maypartiallyrestoreHRandeliminatesensitivitytoPARP-inhibitors(160).
The stabilization of the DNAreplication fork prevents its collapse and subsequent cell
death.Reduced recruitment oftheMRN complex (MRE11/RAD50/NBN)tothestalled
replication fork protects it from degradation and thereby confers PARP-inhibitor
resistance(161).
Upregulation of drug efflux pumps (p-glycoproteins, e.g., MDR1) can contribute to
resistance(162,163).
TheactivationofsignalingcascadescanresultinphosphorylationofPARP1,asreported
forthec-MET(mesenchymalepithelialtransition)kinase.PhosphorylationofPARP1by
MET results in increased enzymatic activity and decreased binding affinity of PARPinhibitors(164).
TheoverexpressionofcertainmicroRNAsmightberelatedtoPARP-inhibitorresistance.
Since miR-622 suppresses NHEJ, its overexpression thereby facilitates HR-mediated
double-strandrepair(165).
TheamountofPARPenzymesexpressedinfluencesPARP-inhibitorsensitivity.Theloss
ofPARP1confersPARP-inhibitorresistance(166).
In1971,nicotinamidewasthefirstPARPinhibitoridentified(167).Furtherdevelopmentsled
tosecond-andthird-generationPARP-inhibitors(168).BeforearoleforPARP-inhibitors
in HR-deficient cancers was suspected, PARP-inhibitors were developed as
chemosensitizers and radiosensitizers (169,170). Accordingly, the first phase I trial
reported results of a PARP-inhibitor and temozolomide in solid cancers in 2005 (171).
Preliminaryresultsofthefirstsingle-agentolaparib phaseI trialwere initiallyreported on
patientsunselectedforBRCAmutation(172).Giventhepreclinicaldatapublishedin2005,
thistrialthenfocusedongermlineBRCA-mutatedpatients(173).ResultsofaphaseIItrialof
single-agentolaparibinpatientswithrecurrentgermlineBRCAmutatedovariancancerwas
published in 2009–2010 (174,175). For further discussion of relevant clinical trials, see
Chapter11.ThesesmallmoleculeinhibitorsofDNArepairarelistedinTable3.4.
Olaparib(AZD-2281,MK07339,Lynparza)
Olaparib is metabolized by the cytochrome CYP3A4, a member of the cytochrome P450
family (CYP450). Potential interactions with other pharmaceuticals that are being
metabolizedbythe sameP450 familyofcytochromesneedto beconsidered.Forexample,
thecommonlyusedantiemeticdrug,aprepitant,stronglyinhibitsCYP3A4,andsimultaneous
administrationcanaffecttheplasmaconcentrationofolaparib.
Niraparib(Zejula)
Unlikeolaparibandrucaparib,niraparibisnotmetabolizedbycytochromeP450enzymes,
butratherbycarboxylesterase-catalyzedamidehydrolysis.Therefore,ithasonlynegligible
effects on the CYP450 system (176). Compared to other PARP-inhibitors, niraparib has
shownthe mostpronouncedthrombocytopenia (177).Abaselinebodyweightof lessthan
77kgandaplateletcountoflessthan150k/mLhavebeenidentifiedaspredictorsofthe
needforniraparibdosereduction(178).ThrombocytopeniatriggeredbyPARP-inhibitorsis
associatedwithareversibledecreaseinmegakaryocyteproliferationandmaturation(179).
Rucaparib(Rubraca)
Incontrasttoolaparibandniraparib,rucaparibinhibitstheenzymePARP3aswell.PARP3
activatesPARP1,evenifitisnotboundtodamagedDNA,whichmightincreasetheeffectof
rucaparib (180). By inhibiting the renal transporters MATE1 and MATE2-K, rucaparib
causesanelevationofserumcreatinine.Rucaparibresultsinanygradehypercholesteremia
in 40–80% of patients (181). Rucaparib and niraparib can lead to elevated liver enzymes
(173).
Veliparib(ABT-888)
VeliparibiscurrentlybeingstudiedinphaseIIItrialsinovariancancer.
Immunotherapy
Cancer immunotherapy has been defined as treatments that use components of the
immune system. In this section, only modalities of cancer immunotherapy in the stricter
sensethatenhanceorstimulatetheimmunesystemasatherapeuticmodalityaredescribed.
Cancer immunotherapy can be classified into active and passive immunotherapy.
Passiveimmunotherapyenhancesexistingantitumorresponsesandincludestheuseof
monoclonal antibodies and cytokines. Active immunotherapy directs the immune
system against specific cancer antigens and includes immune cell therapies and
therapeuticcancervaccines.ImmunotherapeuticagentsaresummarizedinTable3.5.
Becauseof hiscontributionsin thelate 19thcentury,William BradleyColey isrecognized
todayasthe“fatherofcancerimmunotherapy.”In 1893,he reportedthe caseof aGerman
immigrant with a neck sarcoma that was deemed inoperable and yet disappeared after an
erysipelasinfection(182). Coley hypothesized that the immune response provoked by the
bacterialinfectionledtoremissionofthesarcoma.HewentontodevelopColey’stoxins,a
mixture of initially live and later dead bacteria that included the species Streptococcus
pyogenesandSerratiamarcescens.Heusedthetoxinsfortherapeuticpurposes.
Cytokines
The cytokines interleukin-2, interleukin-12 (183), and interferon-α and γ (184–186), have
immune modulatory function and have been used as single-agents or in combination with
othertreatment modalities.Positive resultshave beenreported, mainlyforthe combination
treatments and for their intraperitoneal application (187–190). Since intraperitoneal
chemotherapy has been critically evaluated, the addition of immune modulators in this
settinghasnotbeenafocusofrecentresearch.
MonoclonalAntibodies
Monoclonal antibodies are tools of immunotherapy. As described above, EGFR and
Her2/Neu and VEGF antibodies are predominantly interfering with overexpressed
molecules that are critical for cancer cell proliferation and invasion; they are not
stimulatingtheimmunesystem.However,thisclassificationbecomessomewhatblurred
because of partially overlapping mechanisms. For example, trastuzumab triggers
antibody-dependentcellularcytotoxicity (ADCC)and functionsinpartasan immune
stimulator, while its main mechanism is thought to be the interference with an
upregulating signaling cascade. Antibodies that stimulate the immune system are
presentedbelow.
Oregovomab(OvaRex)
Oregovomab is a mouse monoclonal antibody directed against the membrane bound and
solubleCa-125.Theantigen–antibodycomplextriggersbroadcellularandhumoralimmune
responses. The CA125–oregovomab complex can prime dendritic cells. Anti-idiotypic
antibodiesareformedagainstoregovomabandCa-125whichareabletoinduceFc-mediated
tumorcell killing (191). Improved survival has been notedinovariancancerpatients who
developedspecificB-andT-cellresponsesafteroregovomabinjection(192).Ina phaseIII
trial, oregovomab maintenance therapy after standard adjuvant chemotherapy for patients
withprimaryovariancancerdidnotshowanybenefit(193).InanotherphaseIItrialinthe
same setting, however,simultaneous day infusion with oregovomab on alternate cycles
with adjuvant platinum-based chemotherapy permitted an immune effect and
significantlyimprovedprogression-freesurvival(194).Basedonthesedata,arandomized
phaseIIItrialofcarboplatinandpaclitaxelwithorwithoutoregovomabhasbeeninitiated.
Farletuzumab(MORab-003)
Farletuzumab is a humanized monoclonal IgG1 antibody directed against the folate
receptor (FR). It does not prevent folate binding to the receptor, nor inhibit receptor-
mediated endocytosis (195). Instead, it induces antibody-dependent cellular cytotoxicity
(ADCC), complement-dependent cytotoxicity (CDC) (196,197), and tumor cell autophagy
(198). In a phase II trial, patients with recurrent platinum-sensitive ovarian cancer
treated with farletuzumab and carboplatin and paclitaxel followed by farletuzumab
maintenance therapy showed favorable responses compared to historic controls.
However,inasubsequentphaseIIItrialanalyzingpatientswithrecurrentplatinum-sensitive
ovarian cancer treated with chemotherapy plus farletuzumab or plus a placebo, the
progression-freesurvivaldidnotimprove.Subsequentanalyses showedthatovariancancer
patientswithhigherFRlevelsmaybenefitmorefromfarletuzumabuse(199).
ImmuneCheckpointInhibitors
Negativeregulatorsof the immune system, so-called immunecheckpoints,preventan
overshooting of the immune response with possible self-recognition, and subsequent
autoimmunephenomena. Since cancer antigens may be at times similar to self, immune
checkpoints also limit antitumor responses of the immune system. The inhibition of these
negativeregulatorsunleashestheimmuneantitumorresponse(seeFig.3.3).
Anti–CTLA-4(CytotoxicTLymphocyte-AssociatedProtein4)Antibodies
In1994,itwasdemonstratedforthefirsttimethatCTLA-4playedaninhibitoryroleinthe
regulationoftheT-cellresponse(201).CTLA-4isprimarilyanintracellularprotein.Itscell
surface expression is tightly regulated by restricted trafficking and rapid internalization
(202). It is inducibly expressed by native T cells and constitutively expressed by FoxP3
+
regulatoryTcells(Tregs).UponT-cellactivation,thatis,T-cellreceptorengagementandcostimulation with CD28, CTLA-4 translocates to the plasma membrane. Here, CTLA-4
outcompetesCD28,preventsco-stimulatorysignalsfrombindingandtherebyinhibitstheT
cell.CTLA-4activationarrestsT-cellproliferationandactivation.MicelackingCTLA-4die
ofafulminantlymphocyticinfiltrationofalmostallorgans(203).In1996,JamesAllisonand
colleagues blocked CTLA-4 with antibodies to inhibit its immune suppressive effects and
showedanincreasedantitumorresponse(204).Earlyclinicaltrials haveyielded durable
antitumor responses in solid tumors but also mechanism-related toxicities including
autoimmuneenterocolitis,hepatitis,anddermatitis(205,206).Algorithmicuseofsteroids
has alleviated their autoimmune side effects without abrogating any antitumor response
(207).
Table3.5ImmunotherapeuticAgents
Figure 3.3 Immune checkpoint inhibitors. CTLA-4 (cytotoxic T lymphocyte-associated
protein4) negatively regulates the initial stimulationofTcellsbyantigenpresentingdendritic
cells in lymph nodes. The CTLA-4 antibodies ipilimumab and tremelimumab inhibit this
negativeregulation.TherecirculatingTcellsareactivateduponantigenrecognitionwithinthe
tumor.ThisactivationisphysiologicallyrestrictedbytheinteractionofPD-L1onthetumorcells
andPD-1ontheTcell.Themonoclonalantibodiespembrolizumabandnivolumabbindtothe
PD-1 receptor on the T cell; the monoclonal antibodies avelumab, durvalumab, and
atezolizumab bind to the transmembrane ligand, PD-L1, expressed on the tumor cell. Both
groupsofantibodieshinderstericallytheinteractionofPD-L1 andPD1andtherebyblockthe
negativeregulation of T cells andeffectivelydisinhibit activated T cells. Modifiedfrom (200).
(Reprinted with permission from AAAS, from Ribas A, Wolchok JD. Cancer immunotherapy
usingcheckpointblockade.Science.2018;359(6382):1350–1355.)
Ipilimumab(Yervoy)
Ipilimumab is a fully human monoclonal anti–CTLA-4 IgG1 antibody. It has been
hypothesized that the anti–CTLA-4 antibodies disinhibit the immune response by two
possible mechanisms, (i) interference of the CTLA-4/B7 binding and (ii) depletion of
immunosuppressiveregulatory Tcells (Tregs)via Fc-mediatedantibody-dependentcellular
cytotoxicity(ADCC)andcomplement-dependentcytotoxicity(CDC)(208).
Single-agentipilimumab has beenusedin patients with recurrentovariancancer with only
modest success (209,210). Similarly, it did not show significant single-agent activity in
patientswithrecurrentcervicalcancer,eventhoughitwaswelltoleratedandabletoinduce
animmuneresponse(211).
Tremelimumab
Like ipilimumab, tremelimumab is a fully human monoclonal anti–CTLA-4 antibody.
However,itisthenoncomplement fixing isotype IgG2 and mayhavefewereffects on the
density of Tregs (see above). The experience with tremelimumab in gynecologic
malignanciesisthusfarlimited(212,213).