Towa ds a mo e p ecise he apy in cance : Explo ing
epigene ic complexi y
Fe nando P. Cossío
1,2
, Manel Es elle
3,4,5,6
and
Ma ía Be dasco
7,8
Abs ac
A ple ho a o p eclinical e idences sugges s ha pha maco-
logical a ge ing o epigene ic dys egula ion is a po en s a egy
o comba human diseases. Ne e heless, he implemen a ion
o epid ugs in clinical p ac ice is e y sca ce and mainly limi ed
o haema ological malignancies. In his e iew, we discuss
cu ing-edge s a egies o os e he chemical design, he bio-
logical a ionale and he clinical ial de elopmen o epid ugs.
Speci ically, we ocus on he de elopmen o dual hyb ids o
exploi mul i a ge ing o key epigene ic molecules de egula ed
in cance ; he s udy o epigene ic-syn he ic le hali y in-
e ac ions as a mechanism o add ess loss-o - unc ion mu a-
ions, and he combina ion o epid ugs wi h o he he apies
such as immuno he apy o a oid acqui ed chemo esis ance
and inc ease he apy sensi i i y. By explo ing hese chal-
lenges, among o he s, he ield o epigene ic chemical biology
will inc ease i s po en ial o clinical bene i , and mo e e ec i e
s a egies a ge ing he abe an epigenome in cance a e
likely o be de eloped bo h in haema ological and solid
umou s.
Add esses
1
Kimika Fakul a ea, Kimika O ganikoa I Saila, Uni e sidad del País
Vasco –Euskal He iko Unibe si aea, and Donos ia In e na ional
Physics Cen e (DIPC), San Sebas ián-Donos ia, Spain
2
Cen o de Inno ación en Química A anzada (ORFEO–CINQA),
Spain
3
Cance Epigene ics G oup, Cance and Leukemia Epigene ics and
Biology P og am (PEBCL), Josep Ca e as Leukaemia Resea ch
Ins i u e (IJC), Badalona, Ba celona, Ca alonia, Spain
4
Cen o de In es igación Biomédica en Red Cánce (CIBERONC),
Mad id, Spain
5
Ins i ució Ca alana de Rece ca i Es udis A ança s (ICREA), Ba ce-
lona, Ca alonia, Spain
6
Physiological Sciences Depa men , School o Medicine and Heal h
Sciences, Uni e si y o Ba celona, Ba celona, Ca alonia, Spain
7
Bell i ge Biomedical Resea ch Ins i u e (IDIBELL), Ba celona, Ca a-
lonia, Spain
8
Epigene ic The apies G oup, Expe imen al and Clinical Hema ology
P og am (PHEC), Josep Ca e as Leukaemia Resea ch Ins i u e (IJC),
Badalona, Ba celona, Ca alonia, Spain
Co esponding au ho : Be dasco, Ma ía (mbe dasco@ca e -
as esea ch.o g)
Cu en Opinion in Chemical Biology 2020, 57:41–49
This e iew comes om a hemed issue on Chemical Gene ics and
Epigene ics
Edi ed by Akane Kawamu a and A asu Ganesan
Fo a comple e o e iew see he Issue and he Edi o ial
A ailable online 29 May 2020
h ps://doi.o g/10.1016/j.cbpa.2020.04.008
1367-5931/© 2020 The Au ho (s). Published by Else ie L d. This is an
open access a icle unde he CC BY license (h p://c ea i ecommons.
o g/licenses/by/4.0/).
Keywo ds
Epid ugs, DNA me hyla ion, His one modi ica ions, Dual inhibi o s,
Mul i a ge ing, Syn he ic le hali y, Chemo esis ance, Immuno he apy.
Abb e ia ions
BET, b omo- and ex a- e minal domain p o eins; DNMT, DNA me hyl-
ans e ase; HAT, his one ace yl ans e ase; HDAC, his one deace y-
lase; HDMT, his one deme hylase; HMT, his one me hyl ans e ase;
MBD, me hyl-binding domains p o eins; ROS, eac i e oxygen species.
In oduc ion
Fo he las wo decades, epigene ic dys egula ion has
been ecognized as a key ac o con ibu ing o human
diso de s. This is boos ing an inc easing numbe o
s udies in o he ield o epigene ic d ug disco e y [1,2].
Epid ugs, de ined as small-molecule inhibi o s ha
a ge ei he he epigenome o enzymes wi h epigene ic
ac i i y, ha e been de eloped o he h ee ca ego ies o
epigene ic egula o s (w i e s, eade s and e ase s).
Al hough w i e s a e esponsible o adding chemical
g oups o his ones o DNA (e.g., his one ace yl-
ans e ases (HATs), his one me hyl ans e ases
(HMTs) o DNA me hyl ans e ases (DNMTs); e ase s
emo e hem (e.g., his one deace ylases (HDACs) o
his one deme hylases (HDMTs). In addi ion, epige-
ne ic modi ica ions a e ecognized by a se o eade
domains ha a e ec ui ed o speci ic epigene ic ma ks
and ac as e ec o p o eins (e.g., me hyl-binding do-
mains p o eins o b omo- and ex a- e minal (BETs)
domain p o eins). A p esen , he FDA-app o ed
epid ugs include he apies wi h he ollowing HDAC
inhibi o s: Vo inos a and Romidepsin o e ac o y
cu aneous T cell lymphoma, belinos a o pe iphe al T
cell lymphoma o panobinos a o mul iple myeloma.
App o als also included he DNMT inhibi o Deci a-
bine which is adminis a ed in pa ien s wi h haema o-
logical malignancies, such as myelodysplas ic
synd omes, acu e myeloid leukaemia, and ch onic
myelomonocy ic leukaemia. A e he i s - and second-
gene a ions o epid ugs, possibili ies o epid ug
A ailable online a www.sciencedi ec .com
ScienceDi ec
www.sciencedi ec .com Cu en Opinion in Chemical Biology 2020, 57:41–49
de elopmen a e now being explo ed in e ase s, and
BETand me hyl-binding domains p o eins inhibi o s a e
unde going clinical e alua ion o e icacy in di e en
cance se ings [2].
Despi e hei p omise, he e many challenges o be
esol ed o e icien use o epid ugs in he ea men o
human cance , including he lack o speci ici y o
epid ugs, disappoin ing success in solid umou s and he
acquisi ion o d ug chemo esis ance leading o highe
isk o umou elapse. He ein, we e iew he cu ing-
edge app oaches in he ield o chemical biology and
molecula biology ha a e cu en ly being aken o
imp o e he ansla ion o epid ug he apy in o clinical
p ac ice. Al hough s ill in i s in ancy, he in e es ing
concep o epid ug mul i a ge ing, he po en ial o he
epigene ic-based syn he ic le hali y s a egies and he
use o epid ugs in combina ion wi h o he he apies
(such as immuno he apy) a e in oduced as al e na i es
o op imizing he clinical ansla ion o epigene ic
he apy.
F om he magic bulle pa adigm o
mul i a ge epigene ic inhibi o s
Mul i a ge he apeu ic s a egies can in ol e sepa a e
molecules ha gi e ise o well-known combined he a-
pies. An al e na i e s a egy consis s o inco po a ing wo
biologically ac i e uni s di ec ed o hei espec i e
he apeu ic a ge s. These moie ies a e connec ed by a
space componen bound o bo h uni s by co alen bonds.
This s a egy has yielded dual inhibi o s, designed as
‘inhibi o (1)dspace dinhibi o (2)’ compounds, which
in u n ac agains epigene ic and nonepigene ic enzymes
[3]. In he las h ee yea s, se e al addi ional examples
ha e been epo ed (Figu es 1 and 2).
As a as he design, chemical syn hesis and biological
alida ion o no el epigene ic/nonepigene ic dual
Figu e 1
Dual inhibi o s in ol ing epigene ic and nonepigene ic a ge s (2017–2019). DBD, DNA-binding domain; DNMT1, DNA me hyl ans e ase 1; HAT, his one
ace yl ans e ase; HDAC1, his one deace ylase 1; IDO1, indoleamine 2,3-dioxygenase 1; NAMPT, nico inamide phospho ibosyl ans e ase; PD1,
p og ammed cell dea h p o ein 1; VEGFR, ascula endo helial g ow h ac o ecep o .
42 Chemical gene ics and epigene ics
Cu en Opinion in Chemical Biology 2020, 57:41–49 www.sciencedi ec .com
he apeu ic agen s a e conce ned (Figu e 1), an in e -
es ing no el app oach consis s o inco po a ing in o he
same chemical en i y se e al bioac i e componen s no
connec ed by co alen bonds. Thus, Ruan e al. [4]
syn hesized a eac i e oxygen species (ROS)e esponsi e
polyme by condensa ion o poly inyl alcohol wi h a
bo onic diacid ha c ea es a N1-(4-bo onobenzyl)-N3-
(4-bo onophenyl)-N1,N1,N3,N3- e ame hylp opane-
1,3-diaminium (TSPBA) c oss-linke , which can be
decomposed in i o in he p esence o ROS. This
hyd ogel was combined wi h pH-sensi i e
CaCO
3
nanopa icles (NPs) o gene a e a combined
ROS/H
þ
biosensi i e depo ha can encapsula e bioac-
i e species o be eleased in o umou mic oen i on-
men s. These la e molecules we e Zebula ine [5], a
known deme hyla ing eagen , and an an ibody agains
p og ammed dea h-1 (PD1) ecep o [6], which is
exp essed in immune cells, including CD8þTcells. The
combined Zebula ine-poly inyl alcohol-TSBPA-aPD1-
CaCO
3
-NP chemical en i y 1demons a ed i s e icacy
in he inhibi ion o umou g ow h and in p olonging he
su i al ime o B16F10 melanoma bea ing issues [6].
This app oach es ablishes a link be ween combined and
dual he apies in cance , as well as be ween epigene ic
and immuno he apies (la e discussed in his e iew).
O he ecen de elopmen s in dual epigene ic/nonepi-
gene ic inhibi o s a e ga he ed in Figu e 1. Inhibi o 2is
qui e di e en o o he dual co alen bioac i e mole-
cules because i combines a DNA-binding
domain consis ing o a poly(1H-py ole) oligome and a
HAT inhibi o [7]. This dual molecule esul s in a
sequence-speci ic inhibi o ha shows p omising inhib-
i o y p ope ies and an ip oli e a i e e ec s in he
up egula ion o p53 genes hus ini ia ing p53-dependen
apop osis. Many ecen ly epo ed molecules include
HDACs as epigene ic a ge s. Bo h hyd oxamic acids and
amides de i ed om o ho-phenylenediamines, well-
known chela ing g oups o Zn(II)-dependen HDACs
[2], ha e been epo ed. Dual inhibi o 3includes wo
g oups ha simul aneously inhibi nico inamide
phospho ibosyl ans e ase and HDAC1, hus combining
highly ele an me abolic and epigene ic a ge s [8].
The o me inhibi o y moie y consis s o a subs i u ed
hiou ea and he la e includes he o hophenylene-
amine Zn(II)-chela ing g oup. Bo h uni s a e co alen ly
connec ed by a e y sho pa a-phenylene uni . This
molecule showed excellen ac i i y and e icien ly
induced cell apop osis and au ophagy. In addi ion, i
showed p omising in i o an i umou ac i i y in he
HCT116 xenog a model [8]. In he same ein,
Figu e 2
Dual inhibi o s in ol ing solely epigene ic a ge s (2017–2019). DNMT1, DNA me hyl ans e ase 1; EZH1, enhance zes e homologue 1; EZH2, enhance
zes e homologue 2; HDAC1, his one deace ylase 1; LSD1, lysine speci ic deme hylase 1; G9a (EHMT2), his one–lysine N-me hyl ans e ase 2.
Epid ug de elopmen in ad anced p ecision oncology Cossío e al. 43
www.sciencedi ec .com Cu en Opinion in Chemical Biology 2020, 57:41–49
compound 4shows a design based on he hyd oxamic
g oup as he chela ing g oup o HDAC1. This dual in-
hibi o appea s o be mo e po en han 3, and also
showed p omising esul s wi h he HCT116 xenog a
model [9]. Compound 5also con ains he amide
HDAC1-inhibi o y g oup, whe eas he second bioac i e
moie y consis s o an he e ocyclic oxime ha binds
indoleamine 2,3-dioxygenase 1 [10]. This la e haem-
con aining dioxygenase ca alyses he ans o ma ion o
L-T p in o N- o mylkynu enines, which esul s in yp-
ophan deple ion and subsequen inhibi ion o he p o-
li e a ion o T lymphocy es [10]. The e o e, dual
inhibi o 5also connec s epigene ic and immuno he a-
peu ic a ge s. This compound inhibi ed bo h enzymes
in he nanomola ange (Figu e 1) and showed excellen
in i o an i umou ac i i y in he mu ine LLC umou
model [10]. Finally, compounds 6and 7demons a ed
hei inhibi o y po ency o class I HDACs and ascula
endo helial g ow h ac o (VEGFR) [11]. Inhibi ion o
he i s epigene ic a ge was accomplished in 6by a
moie y analogous o he known HDAC inhibi o MS-275
[12], whe eas he second a ge is inco po a ed in 6and 7
by means o a combined 2-me hyl-2H-imidazole/py im-
idine polyhe e ocycle simila o ha which is p esen in
app o ed VEGFR inhibi o Pazopanib [13]. Bo h com-
pounds exhibi ed HDACi and VEGFRi ac i i ies com-
pa able wi h hose ound o MS-275 and pazopanib,
aside addi ional ac i i ies no p esen in he sepa a e
uni s. In addi ion, compound 5showed good pha maco-
kine ic p o iles and o al bioa ailabili y (72%), as well as a
p omising an i umou e icacy in he HT-29 xenog a
model.
Among dual epigene ic inhibi o s, ecen examples
include a dual inhibi o o he HMTs enhance zes e
homologues 2 and 1 (EHZ2 and EHZ1) igge ing
ime hyla ion o he Lys-27 esidue o his one 3
(H3K27). O e exp ession o EZH2 and subsequen
hype me hyla ion o H3K27 is p esen in he p og es-
sion o PRC2-dependen umou s. Bioa ailable com-
pound 8(also known as UNC1999) [14] inhibi s bo h
EZH2 and EZH1 (Figu e 2). Mos in e es ingly, i
induced an imyeloma in i o ac i i y in combina ion
wi h p o easome inhibi o Bo ezomib [15]. A po en-
ially in e es ing combina ion o epigene ic a ge s as-
socia es me hyla ion p ocesses in his ones and DNA. In
pa icula , he inhibi ion o HMT G9a (also known as
EHMT2) me hyla es H3K9, which is o e exp essed in
many umou s, dec eases cance cell p oli e a ion and
hampe s he de elopmen o me as asis [16,17]. 4-
Aminoquinoline 9(CM-272) is a p omising dual G9a/
DNMT1 inhibi o , wi h po encies in he nanomola
ange o bo h a ge s [16,17]. In addi ion, signi ican ly
p olonged su i al o acu e myeloid leukaemia, Acu e
lymphoblas ic leukemia (ALL) and Di use la ge B-cell
lymphoma (DLBCL) xenogenic models was desc ibed.
O he s uc u al analogues [18]o 9showed also
p omising dual G9a/DNMT1 inhibi o y ac i i y. O he
dual inhibi o s shown in Figu e 2 in ol e HDACs as one
o he classes o epigene ic a ge s. Compounds 10 [19],
11 [20] and 12 [21] inco po a e hyd oxamic acid uni s as
HDAC-chela ing g oups, whe eas 13 [22] possesses he
al e na i e o ho-phenylenediamine uni as he
p e e ed chela ing g oup o HDAC1.Compound 10 also
inhibi s lysine speci ic deme hylase 1 (LSD1), an
enzyme ha is p esen in he CoREST co ep esso
complex and deme hyla es mono- and di-me hyla ed
H3K4. The ans-aminocyclop opyl moie y o 10 is
esponsible o he inhibi ion o LSD1, wi h a po ency
wi hin he low mic omolecula ange [19]. Compound
11 combines HDAC1,6 nM inhibi ion wi h mic omola
binding o DNMT1 [20]. In con as , compound 12
inhibi s bo h HDACs and G9a, hus combining deace-
ylases and me hyl ans e ases as dual a ge s [21].
Finally, compound 13 (Co in) inhibi s HDAC1 and
LSD1, hus a ge ing he CoREST complex by encom-
passing he chie ea u es o En inos a and T anylcy-
p omine [22], and showed e y p omising he apeu ic
po en ial in slowing umou g ow h in a mu ine mela-
noma xenog a .
Ta ge ing loss-o - unc ion by syn he ic
le hali y epigene ic app oaches
Se e al examples o epigene ic he apy ake ad an age
o he mu a ions ound in all majo classes o epigene ic
p o eins and ha e been explo ed as a ge s o he apy
[23]. F om a mechanis ic conside a ion, mu a ions can
be di ided in o wo ca ego ies: loss- o gain-o unc ion
o he epigene ic enzyme. Al hough i is possible o
inhibi gain-o - unc ion o epigene ic enzymes (as
example o e exp ession o he HMTs EZH2 o MLL),
loss-o - unc ion mu a ions a e mo e di icul o a ge .
An inno a i e app oach based on he concep o syn-
he ic le hali y has been implemen ed in ecen yea s
opening up new s a egies in d ug de elopmen .
Syn he ic le hali y e e s o a gene ic in e ac ion be-
ween wo genes in which he loss o one o hem has
li le e ec on cellula iabili y, whe eas loss o bo h
genes leads o cellula le hali y. This in e ac ion p o-
ides a he apeu ic oppo uni y by inhibi ing he second
pa ne (e.g., pha macological inhibi ion) in hose u-
mou s wi h gene ic mu a ions a ec ing he o he pa -
ne . A no mal cell wi hou gene ic mu a ions would
ole a e he pha macological inhibi ion, while i would
be le hal o he umou cell wi hou he wo unc ional
genes (Figu e 3a). A e he i s FDA-app o ed syn-
he ic le hal d ug he apy pai ing BRCA1/2 mu a ions
wi h PARP inhibi o olapa ib ea men in o a ian cance
[24], s udies o syn he ic le hal pai s in ol ing
epigene ic- ela ed syn he ic le hal genes ha e been
44 Chemical gene ics and epigene ics
Cu en Opinion in Chemical Biology 2020, 57:41–49 www.sciencedi ec .com
conduc ed, including syn he ic le hali y be ween
epigene ic mu a ions and epigene ic inhibi o s, epige-
ne ic mu a ions and nonepigene ic inhibi o s and
oncogene mu a ions and epigene ic inhibi o s [25]
(Figu e 3b).
One pionee example o epigene ic- ela ed syn he ic
le hali y en e ing in clinical ials was he use o in-
hibi o s o he HMT DOT1L, such as pinome os a , in
he ea men o MLL- usion leukaemia [26]. The
MLL- usion esul s in DOT1L ec ui men and
epigene ic-media ed ac i a ion o well-known d i e s o
umo igenesis (e.g., HOXA9, MEIS1) oge he wi h
p o eins in ol ed in p o ec ion o MLL usion p o eins
om au ophagic deg ada ion (e.g., LAMP5) [27]. The
pinome os a inhibi ion e ec on DOT1L selec i ely
killed MLL- usion leukaemia cells bu no no mal cells
wi hou he MLL gene ic abe a ions h oughou
down egula ing LAMP5 and enhancing he selec i e
au ophagic deg ada ion o MLL oncop o eins [27].
Addi ional examples o syn he ic le hali y be ween
epigene ic al e a ions and epigene ic inhibi o s exis ,
speci ically in ol ing mu a ions in ch oma in emodel-
ling p o eins. Membe s o he SWI/SNF complex a e
equen ly mu a ed in cance , including mu a ions in he
umou supp esso s ARID1A o SMARCB1 [23]. PRC2 is
ano he c ucial ch oma in complex ha includes he
HMT EZH2, and i s de egula ion is associa ed wi h
mul iple cance s [28]. To no e ha he e is an epigene ic
an agonism be ween SWI/SNF and PRC2 complexes,
which has been he ocus o syn he ic legal s a egies. In
his way, pha macological inhibi ion o EZH2 is a syn-
he ic le hal s a egy in umou s ha bou ing SWI/SNF
mu a ions [28,29]. T ea men wi h GSK126, a speci ic
inhibi o o EZH2, dec ease umo igenesis is p eclinical
models o o a ian umou s wi h ARID1A mu a ions [29].
Recen ly, an elegan wo k pe o med by Meye e al.
[30] desc ibed ele an applica ions o syn he ic
le hali y app oaches in ol ing HAT ac i i ies in lym-
phomas. Inac i a ing mu a ions o he CREBBP and
Figu e 3
a
b
Syn hec le hali y
Epigenec – ela ed syn hec le hali y app oaches
Tumo Cell wi h
selec ed mu aons
Mu GENE A GENE B
Cell Le hali y
X
X
Epigenec mu aon + epigenec inhibi o
•MLL- usion( (HMT) + DOT1L inhibi o (pimenos a )
•ARID1A (HMT) + EZH2 inhibi o (GSK126)
•SMARCB1 (CRF) + EZH2 inhibi o (EPZ-6438)
•CREBBP (HAT) + EP300/CREBBEP inhibi o (CU329)
Epigenec mu aon + non-epigenec inhibi o
•KMT2C (HMT) + PARP inhibi o (olapa ib)
•SETD2 (HMT) + PI3Kβ-AKT inhibi o (TGX221)
Non-Epigenec mu aon + epigenec inhibi o
•GATA3 + G9a-GLP inhibi o (BIX101294)
•TP53 + EZH2 inhibi o (GSK126)
GENE A GENE B
No mal Cell
Cell Viabili y
X
GENE A GENE B
No mal Cell
Cell Viabili y
Tumo Cell wi h mu aons
Mu GENE A GENE B
Cell Viabili y
X
GENE A Mu GENE B
Cell Viabili y
X
Mu GENE A Mu GENE B
Cell Le hali y
XX
Cu en Opinion in Chemical Biology
Epigene ic syn he ic le hali y. (a) Syn he ic le hali y e e s o a gene ic in e ac ion be ween wo genes (e.g., gene A and gene B) in which he loss o gene
A o gene B has li le e ec on cellula iabili y, whe eas loss o bo h genes leads o cellula le hali y. (b) Epigene ic- ela ed syn he ic app oaches as
he apeu ic oppo uni y in umou s wi h speci ic mu a ions. The pha macological inhibi ion o one pa ne o he pai (e.g., pha macological inhibi ion o
gene B in umou s ha bou ing gene A mu a ions) could esul in cellula le hali y. A no mal cell wi hou gene ic mu a ions would ole a e he pha ma-
cological inhibi ion o gene B. CRF, ch oma in emodelling ac o ; HAT, his one ace yl ans e ase; HMT, his one me hyl ans e ase.
Epid ug de elopmen in ad anced p ecision oncology Cossío e al. 45
www.sciencedi ec .com Cu en Opinion in Chemical Biology 2020, 57:41–49
EP300 HATs a e mu ually exclusi e gene ic al e a ions in
di use la ge B cell lymphoma and ollicula lymphoma.
Howe e , ea men s wi h small molecule inhibi o s ha
a e selec i e o CREBBP and EP300 (i.e., he b omo-
domain inhibi o CCS1477 and he p eclinical HAT
domain inhibi o CU329) abolished he EP300-
dependency in CREBBP mu an s and esul ed in
diminished umou p oli e a ion in mu ine models [30].
Nonepigene ic inhibi o s ha e been also explo ed in
syn he ic le hali y he apies in ol ing umou s wi h
epigene ic al e a ions. PARP inhibi o s ha e syn he ic
le hal e ec s wi h epigene ic enzymes in cance . The
HMT KMT2C (also known as MLL3) gene has a high
equency in bladde cance . The educ ion o KMT2C
ac i i y esul s in dec eased H3K27ac-dependen
exp ession o genes om he DNA epai pa hways
(pa icula ly in he homologous ecombina ion pa hway)
associa ed wi h highe endogenous DNA damage and
genomic ins abili y in he umou cells, and conse-
quen ially inc eased sensi i i y o he PARP inhibi o
Olapa ib in epi helial ca cinomas [31]. Simila ly, a mo-
lecula in e ac ion be ween he HMT SETD2, which
ca alyses he me hyla ion a H3K36 en iched a p o-
mo e s wi h ac i e ansc ip ion, and PI3K
b
kinase has
been explo ed in p eclinical models o enal cell ca ci-
noma [32]. T ea men wi h inhibi o s o PI3K
b
/AKT
pa hway causes syn he ic le hali y wi h SET2D loss-o -
unc ion and inc eased umou inhibi ion in enal cance
cells [32].
Finally, a syn he ic le hal in e ac ion be ween an onco-
gene mu a ion (nonepigene ic) and he epigene ic d ug
has been desc ibed o he ansc ip ion ac o GATA3
and he HMTs G9A and GLP (also known as EHMT2
and EHMT1, espec i ely) in b eas cance [33].
In e es ingly, no only loss-o - unc ion bu also gain-o -
unc ion o oncogenes could be exploi ed in epigene ic-
ela ed syn he ic le hali y app oaches. T ea men wi h
EZH2 inhibi o s esul s in dec eased me as a ic
po en ial in TP53-o e exp essing p os a e umou s and
ep esen s new he apeu ic oppo uni ies o ea men
o ad anced solid cance s [34].
Epigene ic he apy in combina ion wi h
o he d ugs o boos immune esponse o
d ug sensi i i y
In he ecen yea s, esul s om p eclinical and phase I/
II clinical ials suppo ha , beyond hei po en ial as
mono he apies, epigene ic d ugs could ha e impo an
oles in combina ion wi h o he an icance he apies.
Epid ugs, especially HDACi and DNMTi, ha e been
es ed in combina ion wi h: chemo he apy (e.g., o i-
nos a plus capeci abine and Cispla in in un esec able
gas ic cance [35]), adio he apy (e.g., o inos a plus
pel ic adio he apy in gas ic cance [36]), ho monal
he apy (e.g., panobinos a plus bicalu amide in
cas a ion- esis an p os a e cance [37]) o a ge ed
he apies (e.g., Abexinos a plus he y osine kinase
inhibi o pazopanib in ad anced enal cell ca cinoma
[38]). A syne gis ic e ec o a ou sensi iza ion o he
cance cell o he gi ing he apy and o o e coming
acqui ed chemo esis ance has been obse ed.
Among he combina o ial possibili ies, enhancing he
an icance e icacy o immuno he apy h ough combi-
na ion wi h epigene ic d ugs is ecei ing he mos
a en ion [39]. Posi i e esul s o he immunogenici y o
umou cells a e desc ibed when epid ugs a e adminis-
a ed oge he wi h immune checkpoin blockade
he apy (an i-PD1/PDL1 he apy in combina ion wi h
HDACi in nonesmall-cell lung cance [40]) and adop i e
cellula immuno he apy (e.g., HDACi plus CD19-CAR
CTL he apy in non-Hodgkin’s lymphoma [41]). A
summa y o he mos ecen examples o clinical ials is
p o ided in Table 1. Al hough he mechanisms o ac ion
by which he epid ug he apies modula e he immune
esponse s ill need u he in es iga ion, he eac i a ion
o umou -su ace an igens, endogenous e o i uses and
p o eins o he majo complex o his ocompa ibili y
Table 1
Examples o cu en clinical ials in ol ing epid ugs in combina ion wi h immuno he apy agen s. BETi, b omodomain inhibi o ; CRC,
colo ec al cance ; DNMTi, DNA me hyl ans e ase inhibi o ; HDACi, his one deace ylase inhibi o ; HDMTi, his one deme hylase inhib-
i o ; HNSCC, head and neck squamous cell ca cinoma; HMTi, his one me hyl ans e ase inhibi o ; SGC, sali a y gland cance ; NSCLC,
non–small-cell lung cance ; RCC, enal cell ca cinoma; UB, u ina y bladde cance .
Clinical ial
iden i ie
Clinical
ial phase
Epigene ic d ug Immuno he apy agen Cance ype S a us
NCT01928576 II Azacy idine (DNMTi), en inos a
(HDACi)
Ni olumab (an i-PD1) NSCLC Rec ui ing
NCT02638090 I/II Vo inos a (HDACi) Pemb olizumab (an i-PD1) NSCLC Rec ui ing
NCT02635061 I ACY 241 (HDACi) Ni olumab (an i-PD1) NSCLC Rec ui ing
NCT03179930 II En inos a (HDACi) Pemb olizumab (an i-PD1) Lymphoma Rec ui ing
NCT02619253 I Vo inos a (HDACi) Pemb olizumab (an i-PD1) RCC, UB Rec ui ing
NCT02453620 I En inos a (HDACi) Ipilimumab (an i-CTLA-4),
ni olumab (an i-PD1)
B eas cance Rec ui ing
46 Chemical gene ics and epigene ics
Cu en Opinion in Chemical Biology 2020, 57:41–49 www.sciencedi ec .com
could be media o s o he inc eased umou isibili y o
he hos immune sys em [42]. In spi e o i s p elimina y
success, some equen limi a ions o epid ugs also need
o be sol ed in combina ional he apy, including he
educ ion o he oxici y and he seconda y e ec s. Im-
p o emen s in he immuno he apy schemes will also
bene i om sys ems biology app oaches. In his ega d, a
ecen ma hema ical model o p edic syne gies be ween
BET inhibi o s and an i-CTLA4 immuno he apy has
been p oposed o he op imiza ion o combina o y
he apy in b eas cance [43].
Conclusions
A simpli ied ision o epigene ic egula ion and he use
o inapp op ia e coho s in clinical ials a e undoub edly
limi ing ac o s o he success o epid ugs as he apeu ic
agen s. A p esen , we a e en isioning an app oach
which mo es “ om he simples o he mos complex”. We a e
accep ing ha epigene ic modi ica ions a e no s and
alone p ocesses because se e al epigene ic p o eins
(and also no epigene ic) con ibu e o egula e ch o-
ma in accessibili y, as do se e al nonepigene ic p o eins.
Inhibi ion o a single epigene ic al e a ion can ha e
global and local e ec s on ch oma in con o ma ion
a ec ing mul iple biological p ocesses (e.g., no only
gene egula ion bu also DNA epai o DNA ecombi-
na ion could be a ec ed a e ea men s) and mul iple
biological pa hways (e.g., he HAT CBP/EP300 ace y-
la es lysine esidues o his ones H3 and H4, as well as
he oncogene p53 [44]). Fu he mo e, he e ec o
a ge ing a speci ic ma k could esul in u he changes
in di e en modi ica ions (e.g., ea men s wi h HDAC
inhibi o s could inc ease ace yla ion o his ones bu also
a ec his one me hyla ion [45]). The e o e, esea ch in
he ield o sys ems biology applied o epigene ic com-
plexes would allow us o exploi he bene i s o a ge ing
complexi y, such as he a o emen ioned s a egies o
de elopmen o dual inhibi o s.
Undoub edly, i is no only a ques ion o chemical d ug
design. Basic esea ch o un a el he mechanisms o
ac ion o umou cell p og ession and esponse o he -
apy (e.g., molecula pa hways associa ed wi h umo al
e asion om he hos immune sys em), he b oade
Table 1 (con inued)
Clinical ial
iden i ie
Clinical
ial phase
Epigene ic d ug Immuno he apy agen Cance ype S a us
NCT03552380 II En inos a (HDACi) Ipilimumab (an i-CTLA-4),
ni olumab (an i-PD1)
RCC Rec ui ing
NCT03250273 II En inos a (HDACi) Ni olumab (an i-PD1) Cholangioca cinoma,
panc ea ic cance
Rec ui ing
NCT03278782 II Romidepsin (HDACi) Pemb olizumab (an i-PD1) Lymphoma Rec ui ing
NCT03150329 I Vo inos a (HDACi) Pemb olizumab (an i-PD1) Lymphoma Rec ui ing
NCT03220477 I Guadeci abine (DNMTi) plus
moce inos a (HDACi)
Pemb olizumab (an i-PD1) NSCLC Rec ui ing
NCT03903458 I Tinos amus ine (HDACi) Ni olumab (an i-PD1) Cu aneous melanoma Rec ui ing
NCT02546986 II CC-486 (DNMTi) o placebo Pemb olizumab (an i-PD1) NSCLC Ac i e, no ec ui ing
NCT02437136 I/II En inos a (HDACi) Pemb olizumab (an i-PD1) NSCLC, cu aneous
melanoma and CRC
Ac i e, no ec ui ing
NCT02538510 I/II Vo inos a (HDACi) Pemb olizumab (an i-PD1) HNSCC, SGC Ac i e, no ec ui ing
NCT02032810 I Panobinos a (HDACi) Ipilimumab (an i-CTLA-4) Cu aneous melanoma Ac i e, no ec ui ing
NCT02909452 I En inos a (HDACi) Pemb olizumab (an i-PD1) Ad anced solid umou s Ac i e, no ec ui ing
NCT02395627 II Vo inos a (HDACi) plus
amoxi en (an i-oes ogen)
Pemb olizumab (an i-PD1) B eas cance Ac i e, no ec ui ing
NCT02512172 I Romidepsin (HDACi),
azacy idine (DNMTi)
Pemb olizumab (an i-PD1) CRC Ac i e, no ec ui ing
NCT02697630 II En inos a (HDACi) Pemb olizumab (an i-PD1) Ocula melanoma Ac i e, no ec ui ing
NCT02915523 I/II En inos a (HDACi) A elumab (an i-PDL1) Epi helial o a ian
cance , pe i oneal
cance
Ac i e, no ec ui ing
NCT02708680 II En inos a (HDACi) A ezolizumab (an i-PDL1) B eas cance Ac i e, no ec ui ing
NCT02220842 I Tazeme os a A ezolizumab (an i-PDL1),
obinu uzumab
Lymphoma Ac i e, no ec ui ing
NCT03525795 I/II CPI-1205 (HMTi) Ipilimumab (an i-CTLA-4) Ad anced solid umou s Ac i e, no ec ui ing
NCT02250326 II CC-486 (DNMTi) o pacli axel
( a ge ed he apy)
Du alumab (an i-PDL1) NSCLC Ac i e, no ec ui ing
NCT02959437 I/II Azaci idine (DNMTi) o
INCB057643 (BETi) o
INCB059872 (HDMTi)
Pemb olizumab (an i-PD1) plus
Epacados a
Ad anced solid umou s Ac i e, no ec ui ing
HDACi, his one deace ylase inhibi o ; DNMTi, DNA me hyl ans e ase inhibi o ; NSCLC, non–small-cell lung cance ; CRC, colo ec al cance ; PD1,
p og ammed cell dea h p o ein 1.
Epid ug de elopmen in ad anced p ecision oncology Cossío e al. 47
www.sciencedi ec .com Cu en Opinion in Chemical Biology 2020, 57:41–49
cha ac e isa ion o he gene ic and epigene ic mu a ions
ac ing as d i e s in a umou cell and a be e s a i i-
ca ion o he pa ien s en e ing clinical ials (i.e.,
de elopmen o p edic i e bioma ke s o esponse)
would con ibu e o he de elopmen o mo e adequa e
clinical ials in ol ing epigene ic d ugs. In summa y,
he s udies e iewed he e sugges p omising oppo u-
ni ies o a ge ing epigene ic al e a ions o make
u he ad ances in p ecision oncology.
Au ho con ibu ions
All au ho s con ibu ed o all aspec s o he manusc ip .
Funding
The au ho s hank CERCA P og amme/Gene ali a de
Ca alunya o ins i u ional suppo . Resea ch a M.B. lab
is suppo ed by Ins i u o de Salud Ca los III co unded
by Eu opean Regional De elopmen Funds (ERDF/
FEDER) a way o build Eu ope (PI15/00638 and PI18/
00910). Resea ch a F.P.C lab is suppo ed by Spanish
Minis e io de Ciencia e Inno acio
´n and FEDER
(CTQ2016-80375-P and CTQ2014-51912-REDC), by
Gobie no Vasco/Eusko Jau la i za (IT-324-07) and by
2020 F amewo k P og amme o he Eu opean Union
(Eu o-Cholangio-Ne CA18122).
Con lic o in e es s a emen
M.B. discloses no con lic s o in e es . F.P.C. and M.E.
a e consul an s o Quima yx.
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