Development of Mechanism-Based Strategies for the Treatment of Advanced Breast Ca

该项目基于以下前提：PI 3 K/AKT通路的异常激活是一种常见特征 在人类乳腺癌的失调信号网络，并负责的关键方面， 转化表型我们已经使用了该途径的特定元件的药理学抑制剂， 询问其功能，并使用所获得的信息来开发新的临床策略。我们有 先前表明，Hsp 90蛋白伴侣是HER 2的折叠和稳定性所必需的， Akt.在第一个资助期，我们发现Hsp 90的天然产物抑制剂诱导HER 2 降解并抑制具有HER 2扩增的乳腺肿瘤细胞中的AKT活化。这导致Dcyclin的丢失 在组织培养和体内， 它们与紫杉烷和抑制血管生成有关。这项工作导致了Hsp 90的1期和2期试验 抑制剂17-AAG，其现在已显示在对抗肿瘤药物耐药的患者中具有显著的抗肿瘤活性。 赫赛汀（曲妥珠单抗）。 这些结果和其他结果表明，赫赛汀耐药肿瘤仍然依赖于HER 2 信号我们假设HER 2激活PI 3 K/AKT信号是其生长所必需的。我们 现在建议使用赫赛汀耐药乳腺癌的实验模型来确定其机制 在这一现象中，PI 3 K/AKT信号传导所起的作用，以及Hsp 90的潜在治疗价值， PI 3 K和AKT抑制剂。PI 3 K/AKT信号传导通过多种机制激活， 乳腺癌：HER 2扩增、PI 3 K突变和PTEN功能下降是最常见的 突出。我们现在计划使用PI 3 K、AKT和mTor的选择性药理学抑制剂来研究 在这些设置中的每一个中PI 3 K/AKT激活的生物化学和功能后果，以确定PI 3 K/AKT激活的生物化学和功能后果。 在体内抑制该途径的可行性，并使用这些数据开发基于机制的组合 利用抑制这些靶点的效果的疗法。

This project is based on the premise that aberrant activation of the PI3K/AKT pathway is a common feature of the dysregulated signaling network in human breast cancers and is responsible for key aspects of the transformed phenotype. We have employed pharmacologic inhibitors of specific elements of this pathway to interrogate its function and used the information obtained to develop novel clinical strategies. We have previously shown that the Hsp90 protein chaperone is required for the folding and stability of HER2 and AKT. In the first funding period, we showed that natural product inhibitors of Hsp90 induce HER2 degradation and inhibit AKT activation in breast tumor cells with HER2 amplification. This leads to loss of Dcyclin expression, G1 arrest, and differentiation of these tumors, in tissue culture and in vivo and sensitizes them to taxanes and to inhibition of angiogenesis. This work led to phase 1 and phase 2 trials of the Hsp90 inhibitor 17-AAG, which has now been shown to have significant antitumor activity in patients resistant to Herceptin (trastuzumab). These results and those of others suggest that Herceptin-resistant tumors remain dependent upon HER2 signaling. We hypothesize that HER2 activation of PI3K/AKT signaling is necessary for their growth. We now propose to use experimental models of Herceptin-resistant breast cancer to determine the mechanism of this phenomenon, the role played by PI3K/AKT signaling, and the potential therapeutic value of Hsp90, PI3K, and AKT inhibitors in this setting. PI3K/AKT signaling is activated by a variety of mechanisms in breast cancer: HER2 amplification, PI3K mutation, and decreased PTEN function are among the most prominent. We now plan to use selective pharmacologic inhibitors of PI3K, AKT, and mTor to study the biochemical and functional consequences of PI3K/AKT activation in each of these settings, to determine the feasibility of inhibiting this pathway in vivo and to use these data to develop mechanism-based combination therapies that exploit the effects of inhibiting these targets.