The novel Hsp90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme.
The novel Hsp90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme.
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DOI：
10.1158/1535-7163.mct-10-0248
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发表时间：
2010-09
影响因子：
5.7
通讯作者：
Charest A
中科院分区：
文献类型：
--
作者：
Zhu H;Woolfenden S;Bronson RT;Jaffer ZM;Barluenga S;Winssinger N;Rubenstein AE;Chen R;Charest A
多形性胶质母细胞瘤（GBM）预后极差。我们现在知道表皮生长因子受体（EGFR）信号通路沿着肿瘤抑制基因p16 Ink 4a/p19 ARF和PTEN的功能丧失在GBM发病机制中起关键作用：启动肿瘤发展的早期阶段、维持肿瘤生长、促进浸润和介导对治疗的抗性。我们最近证明，这种遗传组合足以促进成年小鼠GBM的发展。针对EGFR信号传导途径的单一靶点产生的治疗剂已被证明在GBM治疗中相当低效，表明需要组合治疗方法。同时破坏多种信号传导途径的有效策略是通过抑制分子伴侣热休克蛋白90（Hsp 90）。Hsp 90抑制导致所谓的客户蛋白的降解，其中许多是GBM发病机制的关键效应物。NXD 30001是一种新型的第二代Hsp 90抑制剂，表现出改善的药代动力学参数。在这里，我们证明NXD 30001是体外GBM细胞生长的有效抑制剂，与其抑制GBM生物学的几个关键靶标和调节因子的能力一致。我们还证明了NXD 30001在EGFR驱动的GBM基因工程小鼠模型中的体内疗效。我们的研究结果表明，Hsp 90抑制剂NXD 30001是一种治疗性多价分子，其作用是在其肿瘤发生驱动因素的核心打击GBM，并代表了其用于GBM治疗的令人信服的理由。
Glioblastoma multiforme (GBM) has an abysmal prognosis. We now know that the epidermal growth factor receptor (EGFR) signaling pathway along with loss of function of the tumor suppressor genes p16Ink4a/p19ARF and PTEN play a crucial role in GBM pathogenesis: initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration and mediating resistance to therapy. We have recently demonstrated that this genetic combination is sufficient to promote the development of GBM in adult mice. Therapeutic agents raised against single targets of the EGFR signaling pathway have proven rather inefficient in GBM therapy, demonstrating the need for combinatorial therapeutic approaches. An effective strategy for concurrent disruption of multiple signaling pathways is via the inhibition of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 inhibition leads to the degradation of so-called client proteins of which many are key effectors of GBM pathogenesis. NXD30001 is a novel second generation Hsp90 inhibitor that demonstrates improved pharmacokinetic parameters. Here we demonstrate that NXD30001 is a potent inhibitor of GBM cell growth in vitro consistent with its capacity to inhibit several key targets and regulators of GBM biology. We also demonstrate the efficacy of NXD30001 in vivo in an EGFR driven genetically engineered mouse model of GBM. Our findings establish that the Hsp90 inhibitor NXD30001 is a therapeutically multivalent molecule, whose actions strike GBM at the core of its drivers of tumorigenesis and represent a compelling rationale for its use in GBM treatment.