Research ArticleCancer

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

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Science Translational Medicine  18 Nov 2015:
Vol. 7, Issue 314, pp. 314ra185
DOI: 10.1126/scitranslmed.aac5272

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  • RE: AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer
    • Yixian Zhang, Executive Research Director, The Leukemia & Lymphoma Society
    • Other Contributors:
      • Raj Bandaru, Regulatory Consultant, Accenture Accelerated R&D Services
      • Lee Greenberger, Chief Scientific Officer, The Leukemia & Lymphoma Society

    In the article (1), Hong et al described a very interesting next generation antisense molecule AZD9150 with early evidence of clinical activity in lymphoma and lung cancer. The findings are very exciting because the data not only confirmed previously published results we and others have generated using very similar to LNA (locked nucleic acid) molecules (2-9) , but also for the first time showed evidence of on target effect in cancer patients, validating this strategy. Like LNA, AZD9150 can penetrate certain cell types and exhibit enhanced in vitro and in vivo potency compared to an unmodified first generation phosphorothioated and other second generation ASOs such as 2’-methoxyethyl ASOs (1). The authors have hypothesized that oligonucleotide uptake pathway may be intact in primary tumors and primary tumor explants while the uptake pathway are lost in vitro when establishing cell lines. However, our data do not necessarily support this hypothesis and more careful studies are needed to address this issue. In support of this proposal, we have shown earlier, even with primary tumor cells (10), that the cellular uptake of LNA-oligonucleotides varies tremendously depending on the tissue origin. Our data with 3 different tumor types and multiple samples for each type have shown that primary cultures derived from one cancer type demonstrated strikingly superior sensitivity to LNA oligonucleotide compared to the other two. We do not think this observation can be simply attributed...

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    Competing Interests: None declared.