Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program.
BACKGROUND
ABT-263 is a potent (K(i) < 1 nM) small-molecule BH3 mimetic that inhibits the antiapoptotic proteins Bcl-2, Bcl-x(L) and Bcl-w. The structurally related Bcl-2 inhibitor ABT-737 exhibits single-agent preclinical activity against lymphoma, small-cell lung carcinoma, and chronic lymphocytic leukemia and displays synergistic cytotoxicity with chemotherapeutics and radiation.


METHODS
ABT-263 was tested at concentrations ranging from 1.0 nM to 10.0 microM using 23 cell lines from the PPTP in vitro panel and was tested in 44 xenograft models representing nine distinct histologies using daily gavage administration of ABT-263 (100 mg/kg) or vehicle for 21 days.


RESULTS
ABT-263 was active against approximately one-half of the cell lines of the PPTP in vitro panel. The median IC(50) for all of the lines in the panel was 1.91 microM. ABT-263 induced significant prolongation of the EFS distribution in 9 of 35 (26%) of the solid tumor xenografts, and in 5 of 6 (83%) of the evaluable ALL xenografts. ABT-263 induced no objective responses in the solid tumor panels, but induced CRs in 3 of 6 evaluable xenografts in the ALL panel, including two that were maintained for an additional 3 weeks following treatment cessation.


CONCLUSIONS
ABT-263 demonstrated in vitro activity against a range of cell lines, with the ALL cell lines showing the greatest sensitivity. ABT-263 demonstrated limited single agent in vivo activity against the PPTP's solid tumor panels but showed significant activity against xenografts in the ALL panel.
Lock
Richard
R
Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia. rlock@ccia.unsw.edu.au
Carol
Hernan
H
Houghton
Peter J
PJ
Morton
Christopher L
CL
Kolb
E Anders
EA
Gorlick
Richard
R
Reynolds
C Patrick
CP
Maris
John M
JM
Keir
Stephen T
ST
Wu
Jianrong
J
Smith
Malcolm A
MA
D000814:Aniline Compounds / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C528561:navitoclax