First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy.
Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as "undruggable." We developed a decoy targeting STAT3 and conducted a phase 0 trial. Expression levels of STAT3 target genes were decreased in head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexaethylene glycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development.


CONCLUSIONS
This is the fi rst study of a STAT3-selective inhibitor in humans and the fi rst evidence that a transcription factor decoy can be modifi ed to enable systemic delivery. These findings have therapeutic implications beyond STAT3 to other “undruggable” targets in human cancers.
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Malabika
M
Sen
Sufi M
SM
Thomas
Seungwon
S
Kim
Joanne I
JI
Yeh
Robert L
RL
Ferris
Jonas T
JT
Johnson
Umamaheswar
U
Duvvuri
Jessica
J
Lee
Nivedita
N
Sahu
Sonali
S
Joyce
Maria L
ML
Freilino
Haibin
H
Shi
Changyou
C
Li
Danith
D
Ly
Srinivas
S
Rapireddy
Jonathan P
JP
Etter
Pui-Kai
PK
Li
Lin
L
Wang
Simion
S
Chiosea
Raja R
RR
Seethala
William E
WE
Gooding
Xiaomin
X
Chen
Naftali
N
Kaminski
Kusum
K
Pandit
Daniel E
DE
Johnson
Jennifer R
JR
Grandis
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics*; D011897:Random Allocation; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human