Tumor-targeted SN38 inhibits growth of early stage non-small cell lung cancer (NSCLC) in a KRas/p53 transgenic mouse model.
Tumor-targeted SN38 inhibits growth of early stage non-small cell lung cancer (NSCLC) in a KRas/p53 transgenic mouse model.
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DOI：
10.1371/journal.pone.0176747
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Golemis EA
中科院分区：
文献类型：
--
作者：
Deneka AY;Haber L;Kopp MC;Gaponova AV;Nikonova AS;Golemis EA
非小细胞肺癌(NSCLC)是世界范围内癌症死亡的主要原因，其5年生存率仅为16%。解决非小细胞肺癌死亡率的潜在战略包括改进早期发现和预防，以及开发适合于早期和晚期诊断患者使用的新疗法。控制早期肿瘤的生长可以为患有使他们不适合手术的合并症的患者产生显著的临床益处：然而，由于相关的毒性，许多限制癌症生长的药物在长期使用的情况下或对合并疾病的患者无效。在这项研究中，我们探索了一种最近描述的小分子药物STA-8666作为一种潜在的药物来控制早期肿瘤的生长。STA-8666使用可切割接头将热休克蛋白90(HSP90)与细胞毒性化学物质SN38结合的肿瘤靶向部分合并，并已在使用患者来源和其他异种移植模型治疗胰腺癌、膀胱癌和小细胞肺癌的临床前研究中证明具有高效的肿瘤靶向，具有高效和低毒的特点。使用KRAS基因突变和TrP53基因敲除所产生的NSCLC基因工程模型，我们连续给小鼠在肿瘤诱导后立即给予STA-8666 15周。STA-8666显著减缓了肿瘤的生长速度，并且在延长的给药期内耐受性良好。在肿瘤组织中，STA-8666选择性地诱导DNA损伤和细胞凋亡，并抑制增殖相关蛋白ERK1/2的增殖和磷酸化。相比之下，STA-8666不影响与上皮-间充质转化(EMT)相关的肿瘤特征，如波形蛋白染色程度，也不下调肿瘤HSP90的表达。这些数据表明，STA-8666和其他类似的靶向化合物可能是控制患者群体中早期非小细胞肺癌生长的有用添加剂。
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, with a 5-year survival of only ~16%. Potential strategies to address NSCLC mortality include improvements in early detection and prevention, and development of new therapies suitable for use in patients with early and late stage diagnoses. Controlling the growth of early stage tumors could yield significant clinical benefits for patients with comorbidities that make them poor candidates for surgery: however, many drugs that limit cancer growth are not useful in the setting of long-term use or in comorbid patients, because of associated toxicities. In this study, we explored the use of a recently described small molecule agent, STA-8666, as a potential agent for controlling early stage tumor growth. STA-8666 uses a cleavable linker to merge a tumor-targeting moiety that binds heat shock protein 90 (HSP90) with the cytotoxic chemical SN38, and has been shown to have high efficacy and low toxicity, associated with efficient tumor targeting, in preclinical studies using patient-derived and other xenograft models for pancreatic, bladder, and small cell lung cancer. Using a genetically engineered model of NSCLC arising from induced mutation of KRas and knockout of Trp53, we continuously dosed mice with STA-8666 from immediately after tumor induction for 15 weeks. STA-8666 significantly slowed the rate of tumor growth, and was well tolerated over this extended dosing period. STA-8666 induced DNA damage and apoptosis, and reduced proliferation and phosphorylation of the proliferation-associated protein ERK1/2, selectively in tumor tissue. In contrast, STA-8666 did not affect tumor features, such as degree of vimentin staining, associated with epithelial-mesenchymal transition (EMT), or downregulate tumor expression of HSP90. These data suggest STA-8666 and other similar targeted compounds may be useful additions to control the growth of early stage NSCLC in patient populations.