Home > Organization > Divisions and Independent Research Units > Division of Cancer Therapeutics > Research Projects
Research Projects
Development of cancer therapies using a unique platform
I
n t
he f
ield o
f c
ancer t
herapeutics, w
e a
im t
o d
evelop s
ynthetic l
ethal t
herapies b
ased o
n g
enetic a
bnormalities by m
aking f
ull u
se o
f our p
roprietary c
ancer c
ell l
ine p
anels derived f
rom p
ediatric, j
uvenile, a
nd r
efractory c
ancers, a
s w
ell a
s a d
rug d
iscovery t
arget s
creening s
ystem b
ased o
n our p
roprietary "
paralog s
imultaneous i
nhibition m
ethod". By
utilizing these proprietary platforms, it
is possible to develop the following cancer treatments.
- For clinical drug candidates developed by pharmaceutical companies, etc., we will use a panel of cancer cell lines from various cancer types to identify promising cancer types.
- For specific cancer types, cancer cell line panels and screening systems are used to identify promising drug discovery seeds.
Identification of Suitable Cancer Types Using Cancer Cell Line Panels
The cancer cell line panels we have built so far are constructed from multiple cell lines derived from various cancer types. S
ince w
e h
ave o
btained i
nformation o
n c
ell p
roliferation, g
enetic a
bnormalities, a
nd t
he a
bility t
o t
ransplant t
umorigenic p
roperties of t
hese c
ell l
ines, i
t i
s p
ossible to s
earch f
or t
herapeutic t
argets, t
est d
rug s
usceptibility, a
nd i
nvestigate a
ntitumor e
ffects f
or v
arious p
urposes.S
o f
ar, w
e h
ave d
iscovered d
rug t
argets b
ased o
n g
enetic a
bnormalities i
n s
pecific c
ancer t
ypes. I
n o
rder t
o f
urther d
evelop t
his r
esearch, w
e a
re i
nvestigating t
he p
ossibility o
f e
xpanding t
he i
ndication t
o v
arious c
ancer t
ypes.I
n a
ddition, we h
ave c
onducted d
rug s
electivity s
tudies o
n c
linical d
rug c
andidates u
nder d
evelopment by p
harmaceutical companies b
ased o
n g
enetic a
bnormalities c
haracteristic o
f v
arious c
ancer t
ypes, a
nd h
ave i
dentified p
romising c
ancer t
ypes for t
hose c
linical d
rug c
andidates. In addition, we
are investigating the antitumor effect in vivo models using transplanted tumor models derived from cell lines of
the cancer type.
Identification of drug targets using a unique target search system
The DepMap portal provides information on genetic abnormalities and lethality when human
genes are suppressed genome-wide for
more than 1,000 cell lines. B
y a
nalyzing t
his d
atabase, it i
s a
lso p
ossible t
o i
dentify s
ynthetic l
ethal t
argets b
ased o
n g
enetic a
bnormalities. H
owever, t
argets u
sing t
his d
atabase c
an o
nly b
e f
ound by e
xisting c
ell l
ines a
nd s
uppression o
f a
s
ingle g
ene (
one t
arget f
or o
ne g
enetic a
bnormality: a
o
ne-to-one s
ynthetic l
ethal t
arget).I
n t
he f
ield of c
ancer t
herapeutics, we a
re c
onstructing a c
ell l
ine p
anel c
onsisting o
f c
ell l
ines d
erived f
rom r
are c
ancers a
nd c
ancer p
atients t
hat a
re n
ot u
sed i
n d
atabases. I
n a
ddition, the t
arget s
earch m
ethod u
sed i
n t
he d
atabase c
an search f
or a
t
arget b
y s
uppressing a
s
ingle g
ene, b
ut the t
arget s
earch m
ethod d
eveloped i
n the f
ield o
f c
ancer t
herapy c
an search for a
h
ighly u
nique t
arget by s
imultaneously s
uppressing t
wo g
enes b
ased o
n the "
paralog s
imultaneous i
nhibition m
ethod".Therefore, in the
field of
cancer therapeutics, by
making full use of a
unique platform with a unique cancer cell line panel and a unique screening system, it is possible to search for highly original drug discovery targets that can never be found in public databases.
Development of therapies for childhood cancer and juvenile cancer
Effective treatments for
childhood cancers and juvenile cancers (AYA generation cancers) have been
developed for hematologic cancers, but the
development of treatments for solid tumors such as sarcomas in particular has not progressed much. T
he r
eason f
or t
his m
ay b
e t
hat it i
s a
r
are c
ancer w
ith a
s
mall n
umber o
f p
atients c
ompared t
o a
dult c
ancers, m
aking it d
ifficult to c
onduct c
linical t
rials. I
n p
articular, i
t m
ay b
e d
ifficult t
o c
onduct c
linical t
rials o
f n
ew t
herapeutic d
rugs f
or p
ediatric c
ancer.In the
field of cancer therapeutics, we
aim to develop synthetic lethal therapies for rhabdoid tumors in
children, epithedic sarcoma in juvenile cancers, and ovarian clear cell carcinoma.
Development of synthetic lethal treatment for rhabdoid tumors and epithedioid sarcoma
Rhabdoid tumor and epithedioid sarcoma are rare cancers that affect
about 15 people annually in Japan. S
MARCB1 g
ene i
s t
he c
ausative g
ene that c
auses d
efective g
enetic a
bnormalities in m
ost p
atients w
ith r
habdoid t
umors a
nd e
pithelioid s
arcomas M
r./Ms.. T
o d
ate, we have i
dentified a p
aralog p
air o
f C
BP/p300 as a
p
romising s
ynthetic l
ethal t
arget f
or S
MARCB1-d
eficient r
habdoid t
umors a
nd e
pitherioid s
arcoma. W
e a
re a
lso w
orking w
ith p
harmaceutical c
ompanies t
o d
evelop C
BP/p300 s
imultaneous i
nhibitors.Currently, we
are working on the
search for new therapeutic targets based on the "paralog simultaneous inhibition method" in order to further develop promising therapidoid therapidoid tumors in
SMARCB1-deficient rhabdoid tumors.
Development of synthetic lethal treatment for ovarian clear cell carcinoma
Ovarian clear cell carcinoma is a
rare cancer that
is common in relatively young women in their
20s to 40s. A
RID1A i
s a
t
umor s
uppressor g
ene that causes a
d
efective g
ene a
bnormality i
n a
pproximately 5
0% o
f o
varian c
lear c
ell c
arcinomas. T
o d
ate, w
e have i
dentified g
emcitabine, a G
CLC i
nhibitor, a
G
SH i
nhibitor, a
nd a n
ucleic a
cid m
etabolism i
nhibitor, as a p
romising s
ynthetic l
ethal t
arget f
or A
RID1A-deficient o
varian c
lear c
ell c
arcinoma. I
n a
ddition, we h
ave b
een w
orking w
ith p
harmaceutical c
ompanies t
o d
evelop G
CLC i
nhibitors.Currently, we
are working on the search for new therapeutic targets based on the "paralog simultaneous inhibition method" in order to further develop promising therapies for ARID1A-deficient ovarian clear cell carcinoma.
Development of therapies for refractory cancers
Refractory cancer is a
cancer with a five-year survival rate of less than 50%. There are s
everal r
easons w
hy r
efractory c
ancers a
re i
ntractable, b
ut o
ne r
eason i
s that some of them are a
bnormalities i
n o
ncogenes, a
nd m
ost o
f t
he o
thers a
re a
bnormalities i
n t
umor s
uppressor g
enes. I
n o
ther w
ords, a
n o
ncogene a
bnormality i
s an a
ctivated g
enetic a
bnormality, s
o it i
s p
ossible to t
reat it b
y i
nhibiting t
he p
rotein d
erived f
rom t
he a
ctivated o
ncogene with a
n i
nhibitor. H
owever, i
n t
he c
ase o
f t
umor s
uppressor g
enes, it c
annot b
e i
nhibited w
ith i
nhibitors b
ecause i
t i
s a d
efective t
ype o
f g
enetic a
bnormality. T
herefore, it i
s n
ecessary t
o i
dentify s
ynthetic l
ethal t
argets f
or s
uch d
efective g
enetic a
bnormalities a
nd t
o d
evelop i
nhibitors, a
nd one o
f the r
easons m
ay b
e t
hat t
reatment h
as n
ot p
rogressed.Therefore, as an approach to developing a treatment for refractory cancer, we aim to develop a therapeutic method for refractory cancer by
identifying a synthetic lethal target for defective genetic abnormalities in refractory cancer.
Development of synthetic lethal treatment for non-small cell lung cancer
Among refractory cancers, non
-small cell lung cancer is particularly advanced in cancer genomic medicine. A
pproximately 7
0% o
f n
on-small c
ell l
ung c
ancers h
ave a
ctivated g
enetic a
bnormalities i
n t
umor s
uppressor g
enes, s
uch a
s E
GFR a
ctivation a
bnormalities, A
LK f
usion a
bnormalities, a
nd R
ET f
usion a
bnormalities. M
r./Ms. p
atients w
ith a
bnormalities i
n t
hese o
ncogenes c
an b
e t
reated because m
any i
nhibitors f
or o
ncogene a
bnormalities h
ave b
een d
eveloped. H
owever, i
n the r
emaining 3
0%, there i
s n
o t
reatment b
ased o
n t
he g
enetic a
bnormality because the a
bnormality o
f t
he o
ncogene is n
ot r
ecognized. A
mong t
he 3
0% o
f p
atients w
ithout t
his o
ncogene a
bnormality, t
here i
s a
bout 1
0% o
f the S
MARCA4 g
ene d
efective g
enetic a
bnormality. T
herefore, S
MARCA4-deficient n
on-small c
ell l
ung c
ancer i
s M
r./Ms. o
f p
atients w
ith u
nmet m
edical n
eeds f
or which t
here i
s n
o c
ure d
ue t
o the a
bsence o
f o
ncogene a
bnormalities.T
o d
ate, w
e have i
dentified S
MARCA2, a S
MARCA4 p
aralog, a
s a
s
ynthetic l
ethal t
arget f
or S
MARCA4-d
eficient n
on-small c
ell l
ung c
ancer. I
n a
ddition S
MARCA2 we h
ave b
een w
orking w
ith p
harmaceutical c
ompanies t
o d
evelop d
rug i
nhibitors.We are currently working on the
search for novel therapeutic targets based on simultaneous paralog inhibition to further develop promising therapies for SMARCA4-
deficient non-small cell lung cancer.
Development of synthetic lethal treatment for diffuse gastric cancer
Diffuse gastric cancer is an
undifferentiated type of gastric cancer that accounts for 40% of gastric cancers, and is a
highly malignant and refractory gastric cancer with peritoneal dissemination. I
n a
ddition, s
cirrhous g
astric c
ancer, w
hich a
ccounts f
or 4
0% o
f d
iffuse g
astric c
ancers, i
s an i
ntractable g
astric c
ancer comparable t
o p
ancreatic c
ancer. D
iffuse g
astric c
ancer i
s r
esistant to s
tandard t
reatments f
or g
astric c
ancer, s
uch a
s 5
-FU, o
xaliplatin, a
nd d
ocetaxel, s
o the d
evelopment o
f n
ew t
herapies i
s e
agerly n
eeded. R
ecent s
tudies h
ave s
hown t
hat 3
0% o
f d
iffuse g
astric c
ancers h
ave a
ctivated g
enetic a
bnormalities i
n o
ncogenes s
uch a
s r
eceptor t
yrosine k
inases, a
nd t
reatment b
ased o
n t
hese g
enetic a
bnormalities i
s e
xpected. O
n t
he o
ther h
and, i
n the r
emaining 7
0% o
f d
iffuse g
astric c
ancers, there is n
o a
bnormality i
n t
he o
ncogene a
nd is r
esistant t
o s
tandard t
reatments, s
o n
o p
romising t
reatment h
as b
een e
stablished. H
owever, 4
0% o
f t
hese p
atients (
25% o
f d
iffuse g
astric c
ancers) h
ave a d
eficient g
enetic a
bnormality i
n t
he A
RID1A g
ene. T
herefore, the i
dentification o
f a s
ynthetic l
ethal t
arget f
or A
RID1A-deficient d
iffuse g
astric c
ancer i
s e
xpected t
o l
ead t
o t
he e
stablishment o
f a
t
reatment for r
efractory d
iffuse g
astric c
ancer a
nd e
ven s
cirrhous g
astric c
ancer.We are currently working on the
search for novel therapeutic targets based on simultaneous paralog inhibition using a
panel of patient-derived cell lines from
diffuse gastric cancer to further develop promising therapies for ARID1A-deficient diffuse
gastric cancer.
Development of synthetic lethal treatment for pancreatic cancer
Pancreatic cancer is one of the
most refractory cancers with a
five-
year survival rate of less than 10%. M
ost p
ancreatic c
ancers (
95%) h
ave a
bnormalities i
n t
he K
RAS g
ene. K
RAS i
s a
n o
ncogene a
nd h
as b
een d
ifficult to d
evelop i
nhibitors, b
ut r
ecently, i
nhibitors specific t
o the K
RAS G
12C m
utation h
ave b
een d
eveloped. H
owever, m
ost of t
he K
RAS m
utations i
n p
ancreatic c
ancer a
re m
utations o
ther t
han K
RAS G
12C, s
o treatment w
ith currently d
eveloped K
RAS i
nhibitors i
s n
ot p
ossible. I
n a
ddition t
o the K
RAS g
ene, 3
3% o
f p
ancreatic c
ancers h
ave a d
efective g
ene a
bnormality i
n t
he S
MAD4 g
ene. S
MAD4 i
s a t
ranscription f
actor i
nvolved i
n t
he T
GF-β p
athway t
hat r
egulates g
rowth s
uppression. T
he i
dentification o
f synthetic l
ethal t
argets f
or S
MAD4-deficient p
ancreatic c
ancer i
s e
xpected t
o l
ead t
o t
he e
stablishment o
f a
t
reatment f
or r
efractory p
ancreatic c
ancer.In order to further develop promising therapies for SMAD4-deficient pancreatic cancer, we
are currently working on the search for novel therapeutic targets based on simultaneous paralog inhibition using a
panel of patient-derived cell lines derived from
pancreatic cancer.
Development of synthetic lethal treatment for esophageal cancer
Esophageal cancer is an
intractable cancer that
affects about 570,000 people
annually and kills about 510,000 people
worldwide, and there
is a
desperate need for the development of promising treatments. A
s a
c
haracteristic o
f g
enetic a
bnormalities i
n e
sophageal c
ancer, there a
re a
lmost n
o a
ctive g
enetic a
bnormalities i
n o
ncogenes. I
n o
ther w
ords, m
ost g
enetic a
bnormalities a
re d
efective g
enetic a
bnormalities i
n t
umor s
uppressor g
enes. F
ourteen p
ercent o
f e
sophageal c
ancers h
ave a d
eficient g
enetic a
bnormality i
n t
he h
istone d
emethylase g
ene K
DM6A. T
he i
dentification o
f a
s
ynthetic l
ethal t
arget f
or e
sophageal c
ancer d
eficient in K
DM6A i
s e
xpected t
o l
ead t
o t
he e
stablishment o
f a
t
reatment f
or r
efractory e
sophageal c
ancer.We are currently working to find novel therapeutic targets based on simultaneous paralog inhibition to further develop promising therapies for KDM6A-deficient pancreatic cancer.
