Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.
Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.
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DOI：
10.1371/journal.pone.0087585
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Shacham S
中科院分区：
文献类型：
--
作者：
London CA;Bernabe LF;Barnard S;Kisseberth WC;Borgatti A;Henson M;Wilson H;Jensen K;Ito D;Modiano JF;Bear MD;Pennell ML;Saint-Martin JR;McCauley D;Kauffman M;Shacham S
本研究旨在评价抑制核输出蛋白Exportin 1（XPO 1/CRM 1）功能的选择性核输出抑制剂（SINE）化合物对犬肿瘤细胞系的活性，并在自发性癌症犬中进行KPT-335的I期临床试验，以初步评估生物活性和耐受性。源自非霍奇金淋巴瘤（NHL）、肥大细胞瘤、黑色素瘤和骨肉瘤的犬肿瘤细胞系对纳摩尔浓度的SINE化合物表现出生长抑制和细胞凋亡; NHL细胞对2-42 nM范围内的IC 50浓度特别敏感。KPT-335的I期临床试验在17只患有NHL（初始或复发）、肥大细胞瘤或骨肉瘤的狗中进行。最大耐受剂量为1.75 mg/kg，每周经口给药两次（周一/周四），但在1 mg/kg剂量下观察到生物活性。在9/14只NHL犬中观察到临床获益（CB），包括对治疗的部分应答（PR，n = 2）和疾病稳定（SD，n =7），应答者的中位进展时间（TTP）为66天（范围35-256天）。 在周一/周三/周五给予1.5 mg/kg KPT-335的6只患有NHL的狗中进行剂量扩展研究;在4/6只狗中观察到CB，应答者的中位TTP为83天（范围35-354天）。毒性主要为胃肠道毒性，包括厌食、体重减轻、呕吐和腹泻，可通过支持性治疗、剂量调节和低剂量泼尼松给药进行管理;肝毒性、厌食和体重减轻为剂量限制性毒性。这项研究提供的证据表明，新型口服生物可利用的XPO 1抑制剂KPT-335是安全的，并在相关的自发性大型癌症动物模型中表现出活性。这项研究的数据提供了重要的新信息，为评估SINE化合物在人类癌症中的作用奠定了基础。
The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability. Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2–42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n = 2) and stable disease (SD, n = 7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35–256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35–354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities. This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.
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影响因子：
29.4
作者：
Azmi AS;Aboukameel A;Bao B;Sarkar FH;Philip PA;Kauffman M;Shacham S;Mohammad RM
通讯作者：
Mohammad RM
影响因子：
2.4
作者：
Jubala, CM;Wojcieszyn, JW;Modiano, JF
通讯作者：
Modiano, JF
影响因子：
11.4
作者：
Etchin, J.;Sun, Q.;Kentsis, A.;Farmer, A.;Zhang, Z. C.;Sanda, T.;Mansour, M. R.;Barcelo, C.;McCauley, D.;Kauffman, M.;Shacham, S.;Christie, A. L.;Kung, A. L.;Rodig, S. J.;Chook, Y. M.;Look, A. T.
通讯作者：
Look, A. T.
影响因子：
64.5
作者：
Fornerod, M;Ohno, M;Mattaj, IW
通讯作者：
Mattaj, IW
DOI：
10.1165/ajrcmb/3.5.413
发表时间：
1990-11-01
影响因子：
6.4
作者：
DEVINNEY, R;GOLD, WM
通讯作者：
GOLD, WM