title: AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer.
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.
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.affiliation: UC San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093, USA. rkurzrock@mail.ucsd.edu rmacleod@isisph.com.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Cancer Bioscience Drug Discovery, AstraZeneca Pharmaceuticals, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Woessner
authors.affiliation: Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
authors.affiliation: Mary Crowley Cancer Research Center, 7777 Forest Lane, Dallas, TX 75230, USA.
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Fowler
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Minji
authors.initials: M
authors.lastname: Jo
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Mason
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Hughes
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Fayad
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Sarina
authors.initials: S
authors.lastname: Piha-Paul
authors.affiliation: Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Waltham, MA 02451, USA.
authors.forename: Murali V P
authors.initials: MV
authors.lastname: Nadella
authors.affiliation: Cancer Bioscience Drug Discovery, AstraZeneca Pharmaceuticals, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Morvarid
authors.initials: M
authors.lastname: Mohseni
authors.affiliation: Cancer Bioscience Drug Discovery, AstraZeneca Pharmaceuticals, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Lawson
authors.affiliation: Cancer Bioscience Drug Discovery, AstraZeneca Pharmaceuticals, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Reimer
authors.affiliation: Oncology iMED, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield SK10 4TF, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Blakey
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Hsu
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Revenko
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92008, USA. rkurzrock@mail.ucsd.edu rmacleod@isisph.com.
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D009841:Oligonucleotides / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C000610954:danvatirsen