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Clin Cancer Res. 2016 Oct 15;22(20):5120-5129. doi: 10.1158/1078-0432.CCR-15-3068. Epub 2016 Jun 7.

A Novel HSP90 Inhibitor-Drug Conjugate to SN38 Is Highly Effective in Small Cell Lung Cancer.

Author information

Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Department of Biochemistry, Kazan Federal University, Kazan 420008, Russia.
Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
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.
Nexuspharma Inc., Langhorne, PA 19047.
Synta Pharmaceuticals, Lexington, MA, 02421, USA.
Program in Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Contributed equally



Small cell lung cancer (SCLC) is a highly aggressive disease representing 12% to 13% of total lung cancers, with median survival of <2 years. No targeted therapies have proven effective in SCLC. Although 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.


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 two SCLC xenograft and patient-derived xenograft 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 with 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 with irinotecan.


Together, these results strongly support clinical development of STA-8666 for use in the first- or second-line setting for SCLC. Clin Cancer Res; 22(20); 5120-9. ©2016 AACR.

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