Phase II and Pharmacodynamic Study of Autophagy Inhibition Using Hydroxychloroquine in Patients With Metastatic Pancreatic Adenocarcinoma. (12th May 2014)

• Record Type: Journal Article
• Authors: Wolpin, Brian M.; Rubinson, Douglas A.; Wang, Xiaoxu; Chan, Jennifer A.; Cleary, James M.; Enzinger, Peter C.; Fuchs, Charles S.; McCleary, Nadine J.; Meyerhardt, Jeffrey A.; Ng, Kimmie; Schrag, Deborah; Sikora, Allison L.; Spicer, Beverly A.; Killion, Leah; Mamon, Harvey; Kimmelman, Alec C.
• Is Part Of: Oncologist. Volume 19:Number 6(2014)
• Page Start: 637
• Page End: 638
• Publication Date: 2014-05-12
• Subjects: Oncology -- Periodicals; Tumors -- Periodicals; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Oncology; Tumors; Neoplasms; Electronic journals; Periodicals; Periodicals; 616.994
• DOI: 10.1634/theoncologist.2014-0086
• Languages: English
• ISSNs: 1083-7159

Abstract

Abstract : Background: Autophagy is a catabolic pathway that permits cells to recycle intracellular macromolecules, and its inhibition reduces pancreatic cancer growth in model systems. We evaluated hydoxychloroquine (HCQ), an inhibitor of autophagy, in patients with pancreatic cancer and analyzed pharmacodynamic markers in treated patients and mice. Methods: Patients with previously treated metastatic pancreatic cancer were administered HCQ at 400 mg ( n = 10) or 600 mg ( n = 10) twice daily. The primary endpoint was 2‐month progression‐free survival (PFS). We analyzed peripheral lymphocytes from treated mice to identify pharmacodynamic markers of autophagy inhibition that were then assessed in peripheral lymphocytes from patients. Results: Among 20 patients enrolled, 2 (10%) were without progressive disease at 2 months. Median PFS and overall survival were 46.5 and 69.0 days, respectively. Treatment‐related grade 3/4 adverse events were lymphopenia ( n = 1) and elevated alanine aminotransferase ( n = 1). Tolerability and efficacy were similar at the two dose levels. Analysis of treated murine lymphocytes suggested that LC3‐II expression by Western blot is a reliable marker for autophagy inhibition. Analysis of LC3‐II in patient lymphocytes demonstrated inconsistent autophagy inhibition. Conclusion: Mouse studies identified LC3‐II levels in peripheral lymphocytes as a potential pharmacodynamic marker of autophagy inhibition. In patients with previously treated metastatic pancreatic cancer, HCQ monotherapy achieved inconsistent autophagy inhibition and demonstrated negligible therapeutic efficacy. Abstract : 摘要 背景 . 自噬是一种分解代谢过程，使得细胞内大分子得以回收再利用，自噬抑制在模型系统研究中显示能够阻碍胰腺癌生长。我们在胰腺癌患者中评估了自噬抑制剂羟氯喹（HCQ），并在经治患者与小鼠中分析了药效动力学标记物。 方法 . 入组经治的转移性胰腺癌患者，给予HCQ 400 mg（n = 10）或600 mg（n = 10），每日2次。主要终点为2个月无疾病进展生存期（PFS）。我们针对经治小鼠开展了外周血淋巴细胞分析，以识别自噬抑制的药效动力学标记物，随后在患者外周血淋巴细胞中进行评估。 结果 . 共入组20例患者，2例（10%）在2个月时未出现疾病进展。中位PFS以及总生存期分别为46.5、69.0天。 治疗相关3/4级不良事件为淋巴细胞减少（n = 1），丙氨酸氨基 转移酶升高（n = 1）。两个剂量水平的耐受性和疗效相似。经治小鼠淋巴细胞分析表明，经蛋白印迹法检测的LC3‐II表达可作为自噬抑制的可靠标记物。患者淋巴细胞LC3‐II分析则显示出自噬抑制的不一致性。 结论 . 小鼠研究证实，外周血淋巴细胞LC3‐II水平是自噬抑制的潜在药效动力学标记物。在经治的转移性胰腺癌患者中，HCQ单药治疗并不能普遍达到自噬抑制效果，这提示疗效甚微。 Oncologist 2014; 19:637–638