Development of Mechanism-based Strategies for the Treatment of AdvancedBreast C

开发基于机制的晚期乳腺癌治疗策略

• 批准号: 8741847
• 负责人: NEAL ROSEN
• 金额: $ 54.58万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8741847
• 关键词: AKT inhibition; Attenuated; Biological; Biological Assay; Biology; Breast Cancer Model; Cancer Etiology; Cells; Characteristics; Combined Modality Therapy; Complex; Data; Development; Dose; Drug Targeting; ERBB2 gene; Effectiveness; Enzymes; Event; Feedback; Genetic; Genotype; Goals; Growth; Growth Factor; Human; Lesion; Libraries; Ligands; MEKs; Mammary Neoplasms; Maximum Tolerated Dose; Modality; Modeling; Mutation; Neoplasm Metastasis; Oncogene Proteins; Oncogenes; Oncogenic; Output; PTEN gene; Pathway interactions; Pattern; Pharmaceutical Preparations; Physiological; Physiological Adaptation; Play; Process; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Proteins c-akt; RNA; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Regulation; Role; Schedule; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Transducers; United States; Woman; base; cancer cell; drug efficacy; efficacy testing; human FRAP1 protein; in vivo; inhibitor/antagonist; mTOR inhibition; malignant breast neoplasm; mathematical model; mutant; neoplastic cell; prevent; programs; receptor; response; small hairpin RNA; therapeutic development; therapeutic effectiveness; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumorigenesis

Project summary- Activation of the PI3K signaling pathway is a common event in human breast cancer and is most commonly due to PI3K alpha mutation, HER2 amplification, or PTEN inactivation. Activation of the pathway plays an important role in oncogenesis and tumors with these lesions are dependent on pathway function, whereas tumors in which the pathway is not deregulated are not. While inhibitors of the PI3K pathway effectively suppress growth in vivo, they tend not to induce regression. Our proposal is based on the idea that physiologic adaptation to PI3K pathway inhibitors attenuates the antitumor effects of these drugs and that inhibition of the adaptation will markedly enhance their therapeutic effects. We have shown that constitutive activation of mitogenic signaling by oncoproteins is accompanied by exaggerated feedback inhibition throughout the signaling network. These high levels of feedback play important roles in the biology of transformation and in the response of tumor cells to targeted therapies. High signaling output causes profound inhibition of normal signaling pathways and this causes the cell to be hyperdependent on the oncoprotein dependent pathway. This is responsible in part for the initial sensitivity of these tumors to pharmacologic inhibition of this pathway. But while the tumor is initially sensitive to inhibitors of the activated pathway, inhibition relieves feedback, reactivates upstream signaling and this, we believe, attenuates the antitumor effects of these drugs. Our previous data shows that inhibitors of different nodes in the PI3K pathway (PI3K, AKT, mTOR) all relieve feedback and that combined inhibition of PI3K signaling and adaptive receptor reactivation has enhanced therapeutic activity and causes tumor regression. We now propose in Aim 1 to characterize the relief of feedback responses to selective inhibition of PI3K, AKT or mTOR. In Aim 2 we will use genetic and pharmacologic modalities to determine which adaptations are most responsible for maintaining the survival of the tumor in which the oncogenic pathway has been inhibited. In Aim 3, the data will be used to identify combination therapies based on this concept and test and optimize their antitumor effects in vivo

项目总结-PI 3 K信号通路的激活是人类乳腺癌的常见事件， 最常见的是由于PI 3 K α突变、HER 2扩增或PTEN失活。激活 通路在肿瘤发生中起重要作用，具有这些病变的肿瘤依赖于通路 功能，而肿瘤中的途径没有失调，则没有。虽然PI 3 K通路的抑制剂 有效地抑制体内生长，它们倾向于不诱导退化。我们的建议是基于这样一个想法， 对PI 3 K通路抑制剂的生理适应减弱了这些药物的抗肿瘤作用， 抑制这种适应将显著增强它们的治疗效果。我们已经证明， 癌蛋白对促有丝分裂信号的激活伴随着过度的反馈抑制 整个信令网络。这些高水平的反馈在生物学中起着重要的作用， 转化和肿瘤细胞对靶向治疗的反应。高信号输出导致深刻的 抑制正常的信号传导途径，导致细胞对癌蛋白的过度依赖 依赖路径这是部分负责这些肿瘤的初始敏感性，以药理学 抑制这一途径。但是，虽然肿瘤最初对激活途径的抑制剂敏感， 抑制缓解反馈，重新激活上游信号传导，我们认为，这减弱了抗肿瘤作用。 这些药物的影响。我们以前的数据显示，PI 3 K通路中不同节点的抑制剂（PI 3 K， AKT、mTOR）都能缓解反馈，PI 3 K信号和适应性受体的联合抑制 再活化具有增强的治疗活性并导致肿瘤消退。我们现在在目标1中建议， 表征对PI 3 K、AKT或mTOR的选择性抑制的反馈反应的缓解。在目标2中， 使用遗传学和药理学方法来确定哪些适应是最重要的原因。 维持其中致癌途径已被抑制的肿瘤的存活。在目标3中，数据将 用于鉴定基于该概念的联合疗法，并测试和优化其抗肿瘤作用， 体内