Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non-Small Cell Lung Cancer

被引：511

作者：

Juergens, Rosalyn A. ^{[1
]}

Wrangle, John ^{[1
]}

Vendetti, Frank P. ^{[3
]}

Murphy, Sara C. ^{[1
]}

Zhao, Ming ^{[1
]}

Coleman, Barbara ^{[1
]}

Sebree, Rosa ^{[1
]}

Rodgers, Kristen ^{[2
]}

Hooker, Craig M. ^{[1
]}

Franco, Noreli ^{[1
]}

Lee, Beverly ^{[1
]}

Tsai, Salina ^{[4
]}

Delgado, Igor Espinoza ^{[5
]}

Rudek, Michelle A. ^{[1
]}

Belinsky, Steven A. ^{[6
]}

Herman, James G. ^{[1
]}

Baylin, Stephen B. ^{[1
]}

Brock, Malcolm V. ^{[2
]}

Rudin, Charles M. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Dept Surg, Baltimore, MD 21231 USA

[3] Johns Hopkins Univ, Anticanc Drug Dev Grad Training Program, Baltimore, MD 21231 USA

[4] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21231 USA

[5] NCI, Invest Drug Branch, Bethesda, MD 20892 USA

[6] Lovelace Resp Res Inst, Albuquerque, NM USA

来源：

CANCER DISCOVERY | 2011年 / 1卷 / 07期

基金：

美国国家卫生研究院;

关键词：

HISTONE DEACETYLASE INHIBITION; DNA METHYLATION; PHASE-I; CIRCULATING DNA; 5-AZACYTIDINE; AZACITIDINE; GENES; QUANTIFICATION; PHENYLBUTYRATE; DECITABINE;

D O I：

10.1158/2159-8290.CD-11-0214

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non-small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8-9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy. SIGNIFICANCE: This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit. Cancer Discovery; 1(7); 598-607. (C) 2011 AACR.

引用

页码：598 / 607

页数：10

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