Owonikoko Taofeek K, Zhang Guojing, Kim Hyun S, Stinson Renea M, Bechara Rabih, Zhang Chao, Chen Zhengjia, Saba Nabil F, Pakkala Suchita, Pillai Rathi, Deng Xingming, Sun Shi-Yong, Rossi Michael R, Sica Gabriel L, Ramalingam Suresh S, Khuri Fadlo R
Department of Hematology & Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365C Clifton Road, NE, Suite C3080, Atlanta, GA, 30322, USA.
Department of Radiology, Division of Interventional Radiology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, 30322, USA.
J Transl Med. 2016 May 3;14(1):111. doi: 10.1186/s12967-016-0861-5.
SCLC has limited treatment options and inadequate preclinical models. Promising activity of arsenic trioxide (ASO) recorded in conventional preclinical models of SCLC supported the clinical evaluation of ASO in patients. We assessed the efficacy of ASO in relapsed SCLC patients and in corresponding patient-derived xenografts (PDX).
Single arm, Simon 2-stage, phase II trial to enroll patients with relapsed SCLC who have failed at least one line of therapy. ASO was administered as an intravenous infusion over 1-2 h daily for 4 days in week 1 and for 2 days in weeks 2-6 of an 8-week cycle. Treatment continued until disease progression. Pretreatment tumor biopsy was employed for PDX generation through direct implantation into subcutaneous pockets of SCID mice without in vitro manipulation and serially propagated for five generations. Ex vivo efficacy of cisplatin (3 mg/kg i.p. weekly) and ASO (3.75 mg/kg i.p. every other day) was tested in PDX representative of platinum sensitive and platinum refractory SCLC.
The best response in 17 evaluable patients was stable disease in 2 (12 %), progressive disease in 15 (88 %) patients and median time-to-progression of seven (range 1-7) weeks. PDX was successfully grown in 5 of 9 (56 %) transplanted biopsy samples. Serially-propagated PDXs preserved characteristic small cell histology and genomic stability confirmed by immunohistochemistry, short tandem repeat (STR) profiling and targeted sequencing. ASO showed in vitro cytotoxicity but lacked in vivo efficacy against SCLC PDX tumor growth.
Cisplatin inhibited growth of PDX derived from platinum-sensitive SCLC but was ineffective against PDX from platinum-refractory SCLC. Strong concordance between clinical and ex vivo effects of ASO and cisplatin in SCLC supports the use of PDX models to prescreen promising anticancer agents prior to clinical testing in SCLC patients. Trial Registration The study was registered at http://www.clinicaltrials.gov (NCT01470248).
小细胞肺癌（SCLC）的治疗选择有限，且临床前模型不完善。在SCLC的传统临床前模型中记录到三氧化二砷（ASO）有显著活性，这支持了对ASO在患者中的临床评估。我们评估了ASO在复发SCLC患者及相应的患者来源异种移植瘤（PDX）中的疗效。
采用单臂、Simon两阶段II期试验，纳入至少一线治疗失败的复发SCLC患者。在为期8周的周期中，第1周ASO每天静脉输注1 - 2小时，共4天，第2 - 6周每天输注2天。治疗持续至疾病进展。治疗前进行肿瘤活检，通过直接植入SCID小鼠的皮下囊袋来生成PDX，无需体外操作，并连续传代5代。在代表铂敏感和铂耐药SCLC的PDX中测试顺铂（每周腹腔注射3 mg/kg）和ASO（隔天腹腔注射3.75 mg/kg）的体外疗效。
17例可评估患者中，最佳反应为2例（12%）病情稳定，15例（88%）病情进展，中位疾病进展时间为7周（范围1 - 7周）。9个移植活检样本中有5个（56%）成功培育出PDX。连续传代的PDX保留了特征性的小细胞组织学和基因组稳定性，这通过免疫组织化学、短串联重复序列（STR）分析和靶向测序得以证实。ASO显示出体外细胞毒性，但对SCLC PDX肿瘤生长缺乏体内疗效。
顺铂可抑制铂敏感SCLC来源的PDX生长，但对铂耐药SCLC来源的PDX无效。ASO和顺铂在SCLC中的临床和体外效应之间有很强的一致性，这支持在对SCLC患者进行临床测试之前，使用PDX模型来预筛选有前景的抗癌药物。试验注册 该研究已在http://www.clinicaltrials.gov注册（NCT01470248）。
Zotero 插件
