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


METHODS
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.
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.|Department of Biochemistry, Kazan Federal University, Kazan 420008, Russia.
Anna V
AV
Gaponova
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Anna S
AS
Nikonova
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.|Department of Biochemistry, Kazan Federal University, Kazan 420008, Russia.
Alexander
A
Deneka
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.|Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Meghan C
MC
Kopp
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.
Alexander E
AE
Kudinov
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Natalia
N
Skobeleva
Nexuspharma Inc., Langhorne, PA 19047.
Vladimir
V
Khazak
Synta Pharmaceuticals, Lexington, MA, 02421, USA.
Luisa S
LS
Ogawa
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Kathy Q
KQ
Cai
Program in Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Kelly E
KE
Duncan
Program in Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
James S
JS
Duncan
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Brian L
BL
Egleston
Synta Pharmaceuticals, Lexington, MA, 02421, USA.
David A
DA
Proia
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.
Yanis
Y
Boumber
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Erica A
EA
Golemis
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016190:Carboplatin / Q000627:therapeutic use*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D012118:Resorcinols / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D018841:HSP90 Heat-Shock Proteins; D012118:Resorcinols; C000610389:STA-12-8666; D000077146:Irinotecan; D016190:Carboplatin; D002166:Camptothecin