Stage 1 testing and pharmacodynamic evaluation of the HSP90 inhibitor alvespimycin (17-DMAG, KOS-1022) by the pediatric preclinical testing program

• Published in: Pediatric blood & cancer Vol. 51; no. 1; pp. 34 - 41
• Main Authors: Smith, Malcolm A., Morton, Christopher L., Phelps, Doris A., Kolb, E. Anders, Lock, Richard, Carol, Hernan, Reynolds, C. Patrick, Maris, John M., Keir, Stephen T., Wu, Jianrong, Houghton, Peter J.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-07-2008
• Subjects: alvespimycin; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Benzoquinones - pharmacokinetics; Benzoquinones - pharmacology; Benzoquinones - therapeutic use; Cell Line, Tumor; developmental therapeutics; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Humans; Lactams, Macrocyclic - pharmacokinetics; Lactams, Macrocyclic - pharmacology; Lactams, Macrocyclic - therapeutic use; Mice; Mice, SCID; Neoplasms, Experimental - drug therapy; preclinical testing; Transplantation, Heterologous; Tumor Burden - drug effects
• DOI: 10.1002/pbc.21508
• EISSN: 1545-5017
• ISSN: 1545-5009

Background
Alvespimycin (17‐DMAG, KOS‐1022), a potent small‐molecule inhibitor of the protein chaperone Hsp90, is being developed as an anticancer agent because of the multiple Hsp90 client proteins involved in cancer cell growth and survival.
Procedures
Alvespimycin was tested against the in vitro panel of the Pediatric Preclinical Testing Program (PPTP) at concentrations from 1 nM to 10 µM and was tested against the PPTP's in vivo tumor panels by intraperitoneal administration using a 50 mg/kg BID twice weekly × 6 weeks dose and schedule. Hsp70 induction in tumor and liver tissue was used as a pharmacodynamic measure of Hsp90 inhibition and stress response induction.
Results
Alvespimycin had a median IC50 of 68 nM against the PPTP's in vitro panel, with a trend for lower IC50 values for the rhabdomyosarcoma panel (median IC50 32 nM) and for higher IC50 values for the neuroblastoma panel (median IC50 380 nM). Using the time to event activity measure, alvespimycin had intermediate or high activity against 4 of 28 evaluable solid tumor xenografts, including 3 of 4 alveolar rhabdomyosarcoma xenografts (one with a partial response). Hsp70 induction was observed in tumor tissue from both responding and non‐responding xenografts.
Conclusions
Alvespimycin demonstrated little in vivo antitumor activity against most of the PPTP's preclinical models. The greatest drug effect was observed for the alveolar rhabdomyosarcoma xenografts in the rhabdomyosarcoma panel. Hsp70 induction was observed in responding and non‐responding xenografts, suggesting that tumor‐specific events subsequent to HSP90 inhibition are primary determinants of antitumor activity. Pediatr Blood Cancer 2008;51:34–41. © 2008 Wiley‐Liss, Inc.