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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

1
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
2
Department of Biochemistry, Kazan Federal University, Kazan 420008, Russia.
3
Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
4
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.
5
Nexuspharma Inc., Langhorne, PA 19047.
6
Synta Pharmaceuticals, Lexington, MA, 02421, USA.
7
Program in Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
#
Contributed equally

Abstract

PURPOSE:

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.

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 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.

CONCLUSIONS:

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.

PMID:
27267850
PMCID:
PMC5065742
DOI:
10.1158/1078-0432.CCR-15-3068
[Indexed for MEDLINE]
Free PMC Article

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