Drugs ～Cancer～

Development of antisense oligonucleotide medicine
for the treatment of neuroendocrine cancer
Principal
Investigator

Graduate School of Pharmaceutical Sciences, Osaka University
Specially Appointed Associate Professor Masahito SHIMOJO

Project Outline
OVERVIEW
Smallcell lung cancer (SCLC) is a highly aggressive malignant tumor in lung, which grows rapidly. Although
OVERVIEW
primary
chemotherapy
is oftenthe 5-year
survivalrateinislung,extremely
poor rapidly.
at less Althoughthan 10%.
Small celllung cancer (SCLC)
is aeﬀective,
highly aggressive
malignanttumor
which grows
primary chemotherapy
is ofteneﬀective,medicine
the 5-year
survival
rateexpected.
is extremely
at less
thanidentiﬁed
10%.
Developmentof eﬀective newtherapeuticis thusstrongly
Thepoorresearch
group
Developmentof eﬀective
new therapeutic
medicinethus strongly
research
groupidentiﬁed
Ser/Arg
repetitive
matrix protein
4 (SRRM4)
is highlyis expressedin expected.
SCLC andTheinduces
tumor
formation
and1)
Ser/Arg
repetitive
matrixprotein4(SRRM4)
ishighlyexpressed
inSCLC
andinduces
tumor
formationandgrowth . SRRM4 regulates the alternative splicing of RE1-silencing transcription factor (REST), which
growth 1). theSRRM4
regulates
the alternativetranscription
factorsuppresses
expressionof several
neuronalsplicinggenes. ofIn RE1-silencing
SCLC, neuroendocrine
tumorsare(REST),
formedwhich
by highsuppresses
theexpressionofseveral
neuronalgenes.
InSCLC,
neuroendocrine
tumorsareformed
byhighthe
expression of sREST through the alternative splicing of REST produced by SRRM4. We decided to use
expressionof sREST
through the alternativeof REST
producedby SRRM4.
We Thedecideduse the angapmer
antisenseoligonucleotide(ASO) as a splicing
therapeutic
medicinetargeting
SRRM4.
ASOtocontains
gapmerantisense
oligonucleotide(ASO)asa
therapeutic
medicinetargeting
SRRM4.
TheASO
contains
an inamide-bridged artiﬁcial nucleic acid (AmNA) developed by Dr. Obika, Osaka Univ. The design used theamide-bridged artiﬁcial nucleic acid (AmNA) developed by Dr. Obika, Osaka Univ. The design used the insilicomethod established at Osaka Univ and NIBIOHN. SRRM4 ASO showed tumor regression eﬀect insilico method established at Osaka Univ and NIBIOHN. SRRM4 ASO showed tumor2) regression eﬀect incancer-bearing mice transplanted orthotopically with SCLC-derived cancer cell lines. SRRM4 is also highly
cancer-bearing mice transplanted orthotopically with SCLC-derived cancer cell lines 2). SRRM4 is also highly
expressed in neuroendocrine prostate cancer (NEPC). The clinical trials to make antisense oligonucleotide
expressed in neuroendocrine prostate cancer (NEPC). The clinical trials to make antisense oligonucleotide
medicine targeting SRRM4 the world's ﬁrst antitumor oligonucleotide medicine with excellent eﬃcacy andmedicine targeting SRRM4 the world's ﬁrst antitumor oligonucleotide medicine with excellent eﬃcacy andsafety are expected through clinical and non-clinical studies.
safety are expected through clinical and non-clinical studies.
1)
1)
ShimojoM.M.
etetal.al.Mol
Shimojo
MolCancer
CancerRes.
Res.11:1258
11:1258(2013)(2013)
2)
2)
ShimojoM.
Sci
Rep.
9:7618(2019)
etal.
Shimojo M. et al. Sci Rep. 9:7618 (2019)

Target Disease：neuroendocrine tumour（SCLC、CRPC etc.）
Target Disease：neuroendocrine tumour（SCLC、CRPC etc.）
Patent Information：Domestic patent acquired (patent 6467580). PCT/JP2019/030090 pending.
Patent Information：Domestic patent acquired (patent 6467580). PCT/JP2019/030090 pending.
Technical Features：Antisense oligonucleotide
TechnicalFeatures：Antisense
oligonucleotide
Marketability：New
patients worldwide with lung cancer (1.8 million) and with prostate cancer (1.1 million).
Marketability
patients：
worldwidewithlung cancer (1.8 million) and with prostate cancer (1.1 million).
Challenges ：in New
Development
Non-clinicalstudyChallenges
in Development
study：Non-clinical
Desired contentsof company
collaboration：Collaboration and License out
Desired contents of company collaboration：Collaboration and License out41