Cited by 449RNA Interference and Gene DeliveryCytokine Signaling Pathways and InteractionsDNA and Nucleic Acid Chemistry

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AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer

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Hong, David, Kurzrock, Razelle, Kim, Youngsoo, Woessner, Richard, Younes, Anas, Nemunaitis, John, Fowler, Nathan, Zhou, Tianyuan, Schmidt, Joanna, Jo, Minji, Lee, Samantha J., Yamashita, Mason, Hughes, Steven G., Fayad, Luis, Piha-Paul, Sarina, Nadella, Murali V. P., Mohseni, Morvarid, Lawson, Deborah, Reimer, Corinne, Blakey, David C., Xiao, Xiaokun, Hsu, Jeff, Revenko, Alexey, Monia, Brett P., MacLeod, A. Robert·2015·Science Translational Medicine

DOI 10.1126/scitranslmed.aac5272PMC PMC5279222

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Abstract

Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical data have demonstrated the potent activity of systemically administered ASOs targeted to genes expressed in the liver. We describe the preclinical activity and initial clinical evaluation of a class of ASOs containing constrained ethyl modifications for targeting the gene encoding the transcription factor STAT3, a notoriously difficult protein to inhibit therapeutically. Systemic delivery of the unformulated ASO, AZD9150, decreased STAT3 expression in a broad range of preclinical cancer models and showed antitumor activity in lymphoma and lung cancer models. AZD9150 preclinical activity translated into single-agent antitumor activity in patients with highly treatment-refractory lymphoma and non-small cell lung cancer in a phase 1 dose-escalation study.

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See all 449

Authors: Hong, D., Kurzrock, R., Kim, Y., Woessner, R., Younes, A., Nemunaitis, J., Fowler, N., Zhou, T., Schmidt, J., Jo, M., Lee, S. J., Yamashita, M., Hughes, S. G., Fayad, L., Piha-Paul, S., Nadella, M. V. P., Mohseni, M., Lawson, D., Reimer, C., Blakey, D. C., Xiao, X., Hsu, J., Revenko, A., Monia, B. P., & MacLeod, A. R.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
Moores Cancer Center (US)
Ionis Pharmaceuticals (United States) (US)
AstraZeneca (United States) (US)
Memorial Sloan Kettering Cancer Center (US)
Mary Crowley Cancer Research Center (US)
AstraZeneca (United Kingdom) (GB)
Corresponding author: Hong, David
Kurzrock, Razelle
Kim, Youngsoo
MacLeod, A. Robert
ORCID: Hong, David
Kurzrock, Razelle
Kim, Youngsoo
Younes, Anas
Nemunaitis, John
Fowler, Nathan
Zhou, Tianyuan
Jo, Minji
Lee, Samantha J.
Hughes, Steven G.
Piha-Paul, Sarina
Mohseni, Morvarid
Lawson, Deborah
Reimer, Corinne
Hsu, Jeff
Revenko, Alexey
Monia, Brett P.
MacLeod, A. Robert
Venue: Science Translational Medicine
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2015-11-18
Volume: 7
Issue: 314
Pages: 314ra185-314ra185
ISSN: 1946-6234 (ISSN-L)
1946-6242
DOI: 10.1126/scitranslmed.aac5272
PMC: PMC5279222
OpenAlex: W2174791834
Cited by: 445
References: 60
Citations by year: 2026: 27 · 2025: 29 · 2024: 43 · 2023: 45 · 2022: 41 · 2021: 48 · 2020: 46 · 2019: 52 · 2018: 50 · 2017: 33 · 2016: 30 · 2015: 1
FWCI: 16.51
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.sciencemag.org/about/science-licenses-journal-article-reuse (vor, 366 d)
Locations: Science Translational Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Isis Pharmaceuticals Inc.
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords: antisense oligonucleotides, STAT3 inhibition, lymphoma, non-small cell lung cancer, anticancer activity, treatment-refractory cancer, systemic drug delivery, transcription factor inhibition
MeSH terms: Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Lymphoma, Male, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Oligonucleotides, Time Factors, Down-Regulation, Gene Expression Regulation, Neoplastic, Oligonucleotides, Antisense, Mice, SCID, Mice, Inbred NOD, Treatment Outcome, Apoptosis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Cell Proliferation, STAT3 Transcription Factor, Gene Knockdown Techniques

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AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer

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