PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples.
PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples.
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DOI：
10.1016/j.ejca.2015.02.007
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发表时间：
2015-05
影响因子：
8.4
通讯作者：
Shridhar, Viji
中科院分区：
文献类型：
--
作者：
Winterhoff, Boris;Freyer, Luisa;Hammond, Edward;Giri, Shailendra;Mondal, Susmita;Roy, Debarshi;Teoman, Attila;Mullany, Sally A.;Hoffmann, Robert;von Bismarck, Antonia;Chien, Jeremy;Block, Matthew S.;Millward, Michael;Bampton, Darryn;Dredge, Keith;Shridhar, Viji
尽管抗血管生成药物在卵巢癌中有用，但由于与替代血管生成途径和转移相关的耐药性，疗效仍然有限。因此，我们使用卵巢癌的临床前模型研究了 PG545，这是一种抗血管生成和抗转移药物，目前正处于 I 期临床试验中。使用各种卵巢癌细胞系和肿瘤模型，在体外和体内研究了 PG545 作为单药以及与紫杉醇、顺铂或卡铂联合使用的抗癌活性。 PG545 单独或与化疗药物联合使用，可抑制卵巢癌细胞的增殖，在 A2780 细胞中显示出与紫杉醇的协同作用。 PG545 在体外抑制生长因子介导的细胞迁移并减少 HB-EGF 诱导的 ERK、AKT 和 EGFR 磷酸化，并显着降低肿瘤负荷，在 A2780 模型中与紫杉醇或 SKOV-3 模型中与卡铂联合使用时，肿瘤负荷会增强。而且，在免疫活性的ID8模型中，PG545还显着减少了体内腹水。在 A2780 维持模型中，PG545 以紫杉醇和顺铂治疗开始并在紫杉醇和顺铂治疗后显着改善了总体生存率。 PG545 在临床前模型和一小群晚期癌症患者中增加了血浆 VEGF 水平（和其他目标），这可能代表潜在的反应生物标志物。我们的结果支持 PG545 的临床测试，特别是与紫杉醇联合使用，作为卵巢癌的新型治疗策略。
Despite the utility of antiangiogenic drugs in ovarian cancer, efficacy remains limited due to resistance linked to alternate angiogenic pathways and metastasis. Therefore, we investigated PG545, an anti-angiogenic and anti-metastatic agent which is currently in Phase I clinical trials, using preclinical models of ovarian cancer. PG545's anti-cancer activity was investigated in vitro and in vivo as a single agent, and in combination with paclitaxel, cisplatin or carboplatin using various ovarian cancer cell lines and tumour models. PG545, alone, or in combination with chemotherapeutics, inhibited proliferation of ovarian cancer cells, demonstrating synergy with paclitaxel in A2780 cells. PG545 inhibited growth factor-mediated cell migration and reduced HB-EGF-induced phosphorylation of ERK, AKT and EGFR in vitro and significantly reduced tumour burden which was enhanced when combined with paclitaxel in an A2780 model or carboplatin in a SKOV-3 model. Moreover, in the immunocompetent ID8 model, PG545 also significantly reduced ascites in vivo. In the A2780 maintenance model, PG545 initiated with, and following paclitaxel and cisplatin treatment, significantly improved overall survival. PG545 increased plasma VEGF levels (and other targets) in preclinical models and in a small cohort of advanced cancer patients which might represent a potential biomarker of response. Our results support clinical testing of PG545, particularly in combination with paclitaxel, as a novel therapeutic strategy for ovarian cancer.
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影响因子：
8.8
作者：
Dredge, K.;Hammond, E.;Handley, P.;Gonda, T. J.;Smith, M. T.;Vincent, C.;Brandt, R.;Ferro, V.;Bytheway, I.
通讯作者：
Bytheway, I.
影响因子：
3.7
作者：
Hammond, Edward;Brandt, Ralf;Dredge, Keith
通讯作者：
Dredge, Keith
影响因子：
3.1
作者：
Chen, Gang;Dang, Yi-Wu;Tang, Xiao-Ling
通讯作者：
Tang, Xiao-Ling
影响因子：
1.5
作者：
Bookman, Michael A.
通讯作者：
Bookman, Michael A.
影响因子：
2.6
作者：
Hammond, Edward;Handley, Paul;Bytheway, Ian
通讯作者：
Bytheway, Ian