Aberrant regulation of Notch signaling has been implicated in
tumorigenesis. Proteolytic release of the Notch intracellular domain (NICD) by
gamma-secretase plays a key role in Notch-dependent nuclear signaling.
gamma-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
gamma-secretase inhibitor. The ability of
PF-03084014 to inhibit
gamma-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.