Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia.
Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia.
复制标题
DOI：
10.1158/1535-7163.mct-11-0938
复制
发表时间：
2012-07
影响因子：
5.7
通讯作者：
Ferrando AA
中科院分区：
文献类型：
--
作者：
Samon JB;Castillo-Martin M;Hadler M;Ambesi-Impiobato A;Paietta E;Racevskis J;Wiernik PH;Rowe JM;Jakubczak J;Randolph S;Cordon-Cardo C;Ferrando AA
T细胞急性淋巴细胞白血病和淋巴瘤（T-ALL）是侵袭性血液系统癌症，通常与NOTCH 1的激活突变相关。早期研究将NOTCH 1确定为通过使用γ-分泌酶抑制剂（GSI）治疗T-ALL的有吸引力的治疗靶点。在此，我们在糖皮质激素耐药T-ALL临床前模型中表征了PF-03084014（一种临床相关GSI）与地塞米松之间的相互作用。GSI PF-03084014与糖皮质激素联合治疗在人T-ALL细胞系和原代人T-ALL患者样本中诱导了协同抗白血病作用。PF-03084014加糖皮质激素处理机制诱导糖皮质激素受体和糖皮质激素靶基因的转录上调增加。PF-03084014和糖皮质激素联合治疗在体内高度有效，在T-ALL异种移植模型中肿瘤负荷降低增强。最后，糖皮质激素治疗通过抑制杯状细胞化生有效逆转了PF-03084014诱导的胃肠道毒性。这些结果证明了PF-03084014和糖皮质激素联合治疗糖皮质激素耐药T-ALL的分析。
T-cell acute lymphoblastic leukemias and lymphomas (T-ALL) are aggressive hematologic cancers frequently associated with activating mutations in NOTCH1. Early studies identified NOTCH1 as an attractive therapeutic target for the treatment of T-ALL through the use of γ-secretase inhibitors (GSIs). Here, we characterized the interaction between PF-03084014, a clinically-relevant GSI, and dexamethasone in preclinical models of glucocorticoid-resistant T-ALL. Combination treatment of the GSI PF-03084014 with glucocorticoids induced a synergistic antileukemic effect in human T-ALL cell lines and primary human T-ALL patient samples. Mechanistically PF-03084014 plus glucocorticoid treatment induced increased transcriptional upregulation of the glucocorticoid receptor and glucocorticoid target genes. Treatment with PF-03084014 and glucocorticoids in combination was highly efficacious in vivo, with enhanced reduction of tumor burden in a xenograft model of T-ALL. Finally, glucocorticoid treatment effectively reversed PF-03084014-induced gastrointestinal toxicity via inhibition of goblet cell metaplasia. These results warrant the analysis of PF-03084014 and glucocorticoids in combination for the treatment of glucocorticoid-resistant T-ALL.