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Sci Transl Med. 2015 Nov 18;7(314):314ra185. doi: 10.1126/scitranslmed.aac5272.

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

Author information

1
The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
2
UC San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093, USA. rkurzrock@mail.ucsd.edu rmacleod@isisph.com.
3
Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
4
Cancer Bioscience Drug Discovery, AstraZeneca Pharmaceuticals, 35 Gatehouse Drive, Waltham, MA 02451, USA.
5
Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
6
Mary Crowley Cancer Research Center, 7777 Forest Lane, Dallas, TX 75230, USA.
7
Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Waltham, MA 02451, USA.
8
Oncology iMED, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield SK10 4TF, UK.
9
Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA. rkurzrock@mail.ucsd.edu rmacleod@isisph.com.

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.

PMID:
26582900
PMCID:
PMC5279222
DOI:
10.1126/scitranslmed.aac5272
[Indexed for MEDLINE]
Free PMC Article

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