CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 and Has a Therapeutic Effect on HPV-Induced Neoplasia
CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 and Has a Therapeutic Effect on HPV-Induced Neoplasia
复制标题
DOI：
10.1158/1078-0432.ccr-17-3119
复制
发表时间：
2018-09-15
影响因子：
11.5
通讯作者：
Hagiwara, Masatoshi
中科院分区：
文献类型：
--
作者：
Ajiro, Masahiko;Sakai, Hiroyuki;Hagiwara, Masatoshi
目的：宫颈癌是全世界妇女癌症相关死亡的主要原因之一。本研究的目的是评估新开发的细胞周期蛋白依赖性激酶9 （CDK9）抑制剂FIT-039对人乳头瘤病毒（HPV）感染诱导的宫颈瘤变的治疗效果。实验设计：我们检测了FIT-039对HPV+宫颈癌细胞中HPV基因表达的影响。采用原代角质形成细胞单层和器官型筏培养模型评估HPV病毒复制和宫颈上皮内瘤变（CIN）表型。还进行了FIT-039的临床前药代动力学和毒性试验。最后，利用HPV+宫颈癌异种移植物进一步检测FIT-039在体内的抗HPV作用。结果：fitt -039抑制HPV复制及E6、E7病毒癌基因的表达，恢复HPV+宫颈癌细胞中抑癌因子p53、pRb的表达。在器官型筏培养的CIN模型中证实了FIT-039的治疗效果，其中FIT-039抑制hpv18诱导的异常增生/过度增生，并降低病毒载量。FIT-039也能抑制HPV16（+）的生长，但对HPV+宫颈癌异种移植物没有明显的不良反应。fitt -039的安全性和药代动力学在全身和局部给药中得到证实。结论：CDK9抑制剂FIT-039在临床前研究中显示出有效的抗hpv活性，且无明显毒性。因此，FIT-039有望成为CIN预防宫颈癌的新疗法。(c) 2018年aacr。
Purpose: Cervical cancer is one of the leading causes of cancer-related deaths among women worldwide. The purpose of this study is to assess the therapeutic effect of the newly developed cyclin-dependent kinase 9 (CDK9) inhibitor FIT-039 on cervical neoplasia induced by human papillomavirus (HPV) infection.Experimental Design: We examined FIT-039 for its effect on HPV gene expression in HPV+ cervical cancer cells. Primary keratinocytes monolayer and organotypic raft culture models were used to evaluate HPV viral replication and cervical intraepithelial neoplasia (CIN) phenotypes. Preclinical pharmacokinetics and toxicity tests for FIT-039 were also conducted. Finally, the anti-HPV effect of FIT-039 was further examined in vivo, using HPV+ cervical cancer xenografts.Results: FIT-039 inhibits HPV replication and expression of E6 and E7 viral oncogenes, restoring tumor suppressors p53 and pRb in HPV+ cervical cancer cells. The therapeutic effect of FIT-039 was demonstrated in CIN model of an organotypic raft culture, where FIT-039 suppressed HPV18-induced dysplasia/hyperproliferation with reduction in viral load. FIT-039 also repressed growth of HPV16(+), but not HPV+ cervical cancer xenografts without any significant adverse effects. Safety and pharmacokinetics of FIT-039 were confirmed for systemic and topical routes.Conclusions: The CDK9 inhibitor FIT-039 showed potent anti-HPV activity without significant toxicity in preclinical studies. Thus, FIT-039 is expected to be a novel therapeutic for CIN to prevent cervical cancer. (C) 2018 AACR.