Authors' Affiliations: Developmental Therapeutics Program, Biostatistics Facility, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania; and Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Clin Cancer Res. 2013 Sep 15;19(18):5053-67. doi: 10.1158/1078-0432.CCR-13-1115. Epub 2013 Jul 30.
Epithelial ovarian cancer (EOC) is usually detected at an advanced stage and is frequently lethal. Although many patients respond to initial surgery and standard chemotherapy consisting of a platinum-based agent and a taxane, most experience recurrence and eventually treatment-resistant disease. Although there have been numerous efforts to apply protein-targeted agents in EOC, these studies have so far documented little efficacy. Our goal was to identify broadly susceptible signaling proteins or pathways in EOC.
As a new approach, we conducted data-mining meta-analyses integrating results from multiple siRNA screens to identify gene targets that showed significant inhibition of cell growth. On the basis of this meta-analysis, we established that many genes with such activity were clients of the protein chaperone HSP90. We therefore assessed ganetespib, a clinically promising second-generation small-molecule HSP90 inhibitor, for activity against EOC, both as a single agent and in combination with cytotoxic and targeted therapeutic agents.
Ganetespib significantly reduced cell growth, induced cell-cycle arrest and apoptosis in vitro, inhibited growth of orthotopic xenografts and spontaneous ovarian tumors in transgenic mice in vivo, and inhibited expression and activation of numerous proteins linked to EOC progression. Importantly, paclitaxel significantly potentiated ganetespib activity in cultured cells and tumors. Moreover, combined treatment of cells with ganetespib and siRNAs or small molecules inhibiting genes identified in the meta-analysis in several cases resulted in enhanced activity.
These results strongly support investigation of ganetespib, a single-targeted agent with effects on numerous proteins and pathways, in augmenting standard EOC therapies.
上皮性卵巢癌（EOC）通常在晚期被发现，且常致命。尽管许多患者对初始手术和包含铂类药物和紫杉烷类药物的标准化疗有反应，但大多数患者会复发，并最终产生耐药性疾病。尽管已经有许多将蛋白靶向药物应用于 EOC 的尝试，但这些研究迄今为止证明疗效甚微。我们的目标是鉴定在 EOC 中广泛敏感的信号蛋白或通路。
作为一种新方法，我们进行了数据挖掘的荟萃分析，综合了多个 siRNA 筛选的结果，以鉴定显示出显著抑制细胞生长的基因靶标。基于这项荟萃分析，我们确定了许多具有这种活性的基因是蛋白伴侣 HSP90 的客户。因此，我们评估了 ganetespib，一种具有临床应用前景的第二代小分子 HSP90 抑制剂，用于治疗 EOC，包括单一药物和与细胞毒性和靶向治疗药物联合使用。
Ganetespib 显著降低细胞生长，诱导体外细胞周期停滞和凋亡，抑制体内转基因小鼠的原位异种移植和自发性卵巢肿瘤生长，并抑制与 EOC 进展相关的众多蛋白的表达和激活。重要的是，紫杉醇在培养细胞和肿瘤中显著增强了 ganetespib 的活性。此外，在几种情况下，用 ganetespib 和抑制荟萃分析中鉴定的基因的 siRNA 或小分子联合处理细胞，导致活性增强。
这些结果强烈支持研究 ganetespib，一种具有多种蛋白和通路作用的单靶向药物，以增强标准 EOC 治疗。
