PT  - JOURNAL ARTICLE
AU  - Wei, Ping
AU  - Walls, Marlena
AU  - Qiu, Ming
AU  - Ding, Richard
AU  - Denlinger, Robert H.
AU  - Wong, Anthony
AU  - Tsaparikos, Kosta
AU  - Jani, Jitesh P.
AU  - Hosea, Natilie
AU  - Sands, Michelle
AU  - Randolph, Sophia
AU  - Smeal, Tod
TI  - Evaluation of Selective γ-Secretase Inhibitor PF-03084014 for Its Antitumor Efficacy and Gastrointestinal Safety to Guide Optimal Clinical Trial Design
AID  - 10.1158/1535-7163.MCT-10-0034
DP  - 2010 Jun 01
TA  - Molecular Cancer Therapeutics
PG  - 1618--1628
VI  - 9
IP  - 6
4099  - http://mct.aacrjournals.org/content/9/6/1618.short
4100  - http://mct.aacrjournals.org/content/9/6/1618.full
SO  - Mol Cancer Ther2010 Jun 01; 9
AB  - Aberrant regulation of Notch signaling has been implicated in tumorigenesis. Proteolytic release of the Notch intracellular domain (NICD) by γ-secretase plays a key role in Notch-dependent nuclear signaling. γ-Secretase is an attractive pharmaceutical target for therapeutic intervention in cancer. We describe the potent antitumor effects of PF-03084014, a small molecule that is a reversible, noncompetitive, and selective γ-secretase inhibitor. The ability of PF-03084014 to inhibit γ-secretase activity was shown by the reduction of endogenous NICD levels and by the downregulation of Notch target genes Hes-1 and cMyc in the T-cell acute lymphoblastic leukemia (T-ALL) cell line HPB-ALL. PF-03084014 caused cell growth inhibition of several T-ALL cell lines via cell cycle arrest and induction of apoptosis. PF-03084014 treatment also resulted in robust NICD reduction in HBP-ALL xenograft models. Broad antitumor efficacy at well-tolerated dose levels was observed in six Notch-dependent models. Additional mechanism-of-action studies showed inhibition of tumor cell proliferation and induction of apoptosis in HPB-ALL tumors, suggesting that the antitumor activity of PF-03084014 may be mediated by its direct effects on tumor cell growth or survival. Further studies on PF-03084014–induced gastrointestinal toxicity identified an intermittent dosing schedule that displayed reduced body weight loss and sustained antitumor efficacy. We also showed that glucocorticoids abrogated PF-03084014–induced gastrointestinal toxicity and delayed administration of glucocorticoids did not compromise its protection effect. Collectively, the results show that inhibition of Notch signaling by PF-03084014 while minimizing gastrointestinal toxicity presents a promising approach for development of therapies for Notch receptor–dependent cancers. This compound is being investigated for the treatment of T-ALL and advanced solid tumors in phase I clinical trials. Mol Cancer Ther; 9(6); 1618–28. ©2010 AACR.