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

开发基于机制的晚期乳腺癌治疗策略

• 批准号: 7438486
• 负责人: NEAL ROSEN
• 金额: $ 43.5万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7438486
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; AKT inhibition; AKT1 gene; AKT2 gene; Angiogenesis Inhibition; Animals; Apoptosis; Apoptotic; Binding; Biochemical; Biological Factors; Breast; Breast Cancer Model; Cells; Class; Clinical; Clinical Data; Combined Modality Therapy; Condition; Cytotoxic agent; Data; Development; Dose; ERBB2 gene; Elements; Event; Experimental Models; Funding; G1 Arrest; Goals; Growth; Human; MAP Kinase Gene; Mammary Neoplasms; Maximum Tolerated Dose; Modeling; Molecular Chaperones; Mutation; PH Domain; PI3K/AKT; PTEN gene; Pathway interactions; Patients; Phase; Phase II Clinical Trials; Phenotype; Proteins; Proto-Oncogene Proteins c-akt; Resistance; Roche brand of trastuzumab; Role; Role playing therapy; Schedule; Signal Pathway; Signal Transduction; Stimulus; Taxane Compound; Testing; Therapeutic; Toxic effect; Trastuzumab; Tyrosine Kinase Inhibitor; Work; base; data modeling; desire; in vivo; inhibitor/antagonist; malignant breast neoplasm; mutant; neoplastic cell; novel; research study; taxane; tissue culture; tumor

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.

这个项目的前提是PI3K/AKT通路的异常激活是一个共同的特征 在人类乳腺癌中调节失调的信号网络，并负责 转化的表型。我们已经使用了这一途径的特定元件的药物抑制剂来 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 先前研究表明，Hsp90蛋白伴侣对于HER2和HER2的折叠和稳定性是必需的。 AKT。在第一个资助期，我们发现hsp90的天然产物抑制物可以诱导her2。 HER2扩增抑制乳腺肿瘤细胞AKT的降解和激活这会导致DCyclin的丢失 这些肿瘤在组织培养、体内和致敏中的表达、G1期停滞和分化 它们与紫杉烷和抑制血管生成有关。这项工作导致了Hsp90的第一阶段和第二阶段的试验 抑制剂17-AAG，现已被证明对耐药患者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，对赫赛汀耐药的肿瘤仍然依赖于HER2 发信号。我们推测HER2激活PI3K/AKT信号对它们的生长是必要的。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 PI3K/AKT信号转导途径的作用，以及Hsp90的潜在治疗价值。 PI3K和AKT抑制剂在这种情况下。PI3K/AKT信号被多种机制激活 乳腺癌：HER2基因扩增、PI3K突变和PTEN功能降低是最常见的 很突出。我们现在计划使用PI3K，AKT和mTOR的选择性药物抑制剂来研究 在这些环境中，PI3K/AKT激活的生化和功能后果，以确定 在体内抑制这一途径的可行性并利用这些数据开发基于机制的结合 利用抑制这些靶点的效果的疗法。