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A Novel HSP90 Inhibitor-Drug Conjugate to SN38 Is Highly Effective in Small Cell Lung Cancer
Journal article   Open access   Peer reviewed

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

Anna V Gaponova, Anna S Nikonova, Alexander Deneka, Meghan C Kopp, Alexander E Kudinov, Natalia Skobeleva, Vladimir Khazak, Luisa S Ogawa, Kathy Q Cai, Kelly E Duncan, …
Clinical cancer research, v 22(20), pp 5120-5129
15 Oct 2016
DOI: https://doi.org/10.1158/1078-0432.CCR-15-3068
PMID: 27267850
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1158/1078-0432.ccr-15-3068View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Animals Antineoplastic Agents, Phytogenic - therapeutic use Apoptosis - drug effects Camptothecin - analogs & derivatives Camptothecin - therapeutic use Carboplatin - therapeutic use Cell Cycle Checkpoints - drug effects Cell Line, Tumor DNA Damage - drug effects Drug Delivery Systems - methods Drug Synergism Female HSP90 Heat-Shock Proteins - antagonists & inhibitors Humans Lung Neoplasms - drug therapy Mice Mice, SCID Resorcinols - therapeutic use Signal Transduction - drug effects Small Cell Lung Carcinoma - drug therapy Xenograft Model Antitumor Assays
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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#3 Good Health and Well-Being

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Industry collaboration
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Web of Science research areas
Oncology
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