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      A novel HSP90 inhibitor-drug conjugate to SN38 is highly effective in small cell lung cancer (SCLC)

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          Abstract

          Purpose

          Small cell lung cancer (SCLC) is a highly aggressive disease representing 12-13% of total lung cancers, with median survival <2 years. No targeted therapies have proven effective in SCLC. While most patients respond initially to cytotoxic chemotherapies, resistance rapidly emerges, response to second line agents is limited, and dose-limiting toxicities (DLT) are a major issue. This study performs preclinical evaluation of a new compound, STA-8666, in SCLC.

          Experimental Design

          To avoid DLT for useful cytotoxic agents, the recently developed drug STA-8666 combines a chemical moiety targeting active HSP90 (concentrated in tumors) fused via cleavable linker to SN38, the active metabolite of irinotecan. We compare potency and mechanism of action of STA-8666 and irinotecan in vitro and in vivo.

          Results

          In 2 SCLC xenograft and patient-derived xenograft (PDX) models, STA-8666 was tolerated without side effects up to 150 mg/kg. At this dose, STA-8666 controlled or eliminated established tumors whether used in a first line setting, or in tumors that had progressed following treatment on standard first and second line agents for SCLC. At 50 mg/kg, STA-8666 strongly enhanced the action of carboplatin. Pharmacokinetic profiling confirmed durable STA-8666 exposure in tumors compared to irinotecan. STA-8666 induced a more rapid, robust, and stable induction of cell cycle arrest, expression of signaling proteins associated with DNA damage and cell cycle checkpoints, and apoptosis in vitro and in vivo, in comparison to irinotecan.

          Conclusions

          Together, these results strongly support clinical development of STA-8666 for use in the first or second line setting for SCLC.

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          Author and article information

          Journal
          9502500
          8794
          Clin Cancer Res
          Clin. Cancer Res.
          Clinical cancer research : an official journal of the American Association for Cancer Research
          1078-0432
          21 June 2016
          7 June 2016
          15 October 2016
          15 October 2017
          : 22
          : 20
          : 5120-5129
          Affiliations
          [1 ]Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
          [2 ]Program in Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
          [3 ]Department of Biochemistry, Kazan Federal University, Kazan 420008, Russia
          [4 ]Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA 19129, USA
          [5 ]Nexuspharma Inc., Langhorne, PA 19047
          [6 ]Synta Pharmaceuticals, Lexington, MA, 02421, USA
          [7 ] University of New Mexico Comprehensive Cancer Center, University of New Mexico School of Medicine, Division of Hematology/Oncology, Department of Internal Medicine, Albuquerque, NM 87131
          Author notes
          [* ]corresponding author: Erica Golemis, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111, Tel: 215-728-2860 (EAG), Erica.Golemis@ 123456fccc.edu (EAG)
          Article
          PMC5065742 PMC5065742 5065742 nihpa794588
          10.1158/1078-0432.CCR-15-3068
          5065742
          27267850
          Categories
          Article

          irinotecan, STA-8666, small cell lung cancer

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