Oncology Research Unit and Drug Safety, Pfizer Global Research and Development, La Jolla, CA 92129, USA.
Clin Cancer Res. 2012 Sep 15;18(18):5008-19. doi: 10.1158/1078-0432.CCR-12-1379. Epub 2012 Jul 17.
We aimed to assess the biologic activity of PF-03084014 in breast xenograft models. The biomarkers for mechanism and patient stratification were also explored.
The in vitro and in vivo properties of PF-03084014 were investigated. The mRNA expressions of 40 key Notch pathway genes at baseline or after treatment were analyzed to link with the antitumor efficacy of PF-03084014 in a panel of breast cancer xenograft models.
In vitro, PF-03084014 exhibited activity against tumor cell migration, endothelial cell tube formation, and mammosphere formation. In vivo, we observed apoptosis, antiproliferation, reduced tumor cell self-renewal ability, impaired tumor vasculature, and decreased metastasis activity after the treatment of PF-03084014. PF-03084014 treatment displayed significant antitumor activity in 10 of the 18 breast xenograft models. However, the antitumor efficacy in most models did not correlate with the in vitro antiproliferation results in the corresponding cell lines, suggesting the critical involvement of tumor microenvironment during Notch activation. In the tested breast xenograft models, the baseline expressions of the Notch receptors, ligands, and the cleaved Notch1 failed to predict the antitumor response to PF-03084014, whereas several Notch pathway target genes, including HEY2, HES4, and HES3, strongly corresponded with the response with a P value less than 0.01. Many of the best molecular predictors of response were also significantly modulated following PF-03084014 treatment.
PF-03084014 showed antitumor and antimetastatic properties via pleiotropic mechanisms. The Notch pathway downstream genes may be used to predict the antitumor activity of PF-03084014 and enrich for responders among breast cancer patients.
评估 PF-03084014 在乳腺癌异种移植模型中的生物学活性。还探索了用于机制和患者分层的生物标志物。
研究了 PF-03084014 的体外和体内特性。分析了一组乳腺癌异种移植模型中基线或治疗后 40 个关键 Notch 通路基因的 mRNA 表达，以与 PF-03084014 的抗肿瘤疗效相关联。
在体外，PF-03084014 对肿瘤细胞迁移、内皮细胞管形成和乳腺球体形成具有活性。在体内，我们观察到细胞凋亡、抗增殖、肿瘤细胞自我更新能力降低、肿瘤血管受损以及 PF-03084014 治疗后转移活性降低。PF-03084014 在 18 个乳腺癌异种移植模型中的 10 个模型中显示出显著的抗肿瘤活性。然而，大多数模型中的抗肿瘤疗效与相应细胞系中体外抗增殖结果不相关，这表明 Notch 激活过程中肿瘤微环境的关键参与。在所测试的乳腺癌异种移植模型中，Notch 受体、配体和裂解的 Notch1 的基线表达未能预测对 PF-03084014 的抗肿瘤反应，而一些 Notch 通路靶基因，包括 HEY2、HES4 和 HES3，与反应强烈相关，P 值小于 0.01。许多最佳的分子反应预测因子在 PF-03084014 治疗后也显著发生了调节。
PF-03084014 通过多效机制显示出抗肿瘤和抗转移特性。Notch 通路下游基因可用于预测 PF-03084014 的抗肿瘤活性，并在乳腺癌患者中富集应答者。
