Department of Pathology, Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
Mol Cancer Ther. 2012 Jul;11(7):1565-75. doi: 10.1158/1535-7163.MCT-11-0938. Epub 2012 Apr 13.
T-cell acute lymphoblastic leukemias (T-ALL) and lymphomas 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 (GSI). 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.
T 细胞急性淋巴细胞白血病（T-ALL）和淋巴瘤是侵袭性血液系统癌症，常与 NOTCH1 的激活突变有关。早期研究表明，通过使用γ-分泌酶抑制剂（GSI），NOTCH1 是治疗 T-ALL 的有吸引力的治疗靶点。在这里，我们在糖皮质激素耐药性 T-ALL 的临床前模型中，对 PF-03084014（一种临床相关的 GSI）和地塞米松之间的相互作用进行了表征。GSI PF-03084014 与糖皮质激素联合治疗在人 T-ALL 细胞系和原发性人 T-ALL 患者样本中诱导了协同的抗白血病作用。从机制上讲，PF-03084014 加糖皮质激素治疗诱导了糖皮质激素受体和糖皮质激素靶基因的转录上调。PF-03084014 和糖皮质激素联合治疗在体内非常有效，在 T-ALL 的异种移植模型中，肿瘤负担的减少得到了增强。最后，糖皮质激素治疗通过抑制杯状细胞化生有效地逆转了 PF-03084014 诱导的胃肠道毒性。这些结果证明了分析 PF-03084014 和糖皮质激素联合治疗糖皮质激素耐药性 T-ALL 的合理性。
