Faculty Collaboration Database

AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med 2015 Nov 18;7(314):314ra185

Date

11/20/2015

Pubmed ID

26582900

Pubmed Central ID

PMC5279222

DOI

10.1126/scitranslmed.aac5272

Scopus ID

2-s2.0-84947724597 (requires institutional sign-in at Scopus site)   346 Citations

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.

Author List

Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, Fowler N, Zhou T, Schmidt J, Jo M, Lee SJ, Yamashita M, Hughes SG, Fayad L, Piha-Paul S, Nadella MV, Mohseni M, Lawson D, Reimer C, Blakey DC, Xiao X, Hsu J, Revenko A, Monia BP, MacLeod AR

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Agents
Apoptosis
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Cell Proliferation
Down-Regulation
Female
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Lung Neoplasms
Lymphoma
Male
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, Nude
Mice, SCID
Middle Aged
Oligonucleotides
Oligonucleotides, Antisense
STAT3 Transcription Factor
Time Factors
Treatment Outcome
Tumor Burden
Xenograft Model Antitumor Assays