TY - JOUR
T1 - Stage 1 testing and pharmacodynamic evaluation of the HSP90 inhibitor alvespimycin (17-DMAG, KOS-1022) by the pediatric preclinical testing program
AU - Smith, Malcolm A.
AU - Morton, Christopher L.
AU - Phelps, Doris A.
AU - Kolb, E. Anders
AU - Lock, Richard
AU - Carol, Hernan
AU - Reynolds, C. Patrick
AU - Maris, John M.
AU - Keir, Stephen T.
AU - Wu, Jianrong
AU - Houghton, Peter J.
PY - 2008/7
Y1 - 2008/7
N2 - 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 x 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 IC 50 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.
AB - 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 x 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 IC 50 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.
KW - Alvespimycin
KW - Developmental therapeutics
KW - Preclinical testing
UR - http://www.scopus.com/inward/record.url?scp=44149091042&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44149091042&partnerID=8YFLogxK
U2 - 10.1002/pbc.21508
DO - 10.1002/pbc.21508
M3 - Article
C2 - 18260120
AN - SCOPUS:44149091042
SN - 1545-5009
VL - 51
SP - 34
EP - 41
JO - Pediatric Blood and Cancer
JF - Pediatric Blood and Cancer
IS - 1
ER -