Overcoming Resistance to Standard HER2-Directed Therapies for Breast Cancer

克服乳腺癌标准 HER2 导向疗法的耐药性

• 批准号: 8607754
• 负责人: THOMAS M ROBERTS
• 金额: $ 27.06万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607754
• 关键词: 1-Phosphatidylinositol 3-Kinase; Bypass; Clinical; Clinical Data; Clinical Trials; Data; Disease; ERBB2 gene; Genetically Engineered Mouse; Mediator of activation protein; Methods; Mutation; Outcome; PIK3CA gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphatidylinositide 3-Kinase Inhibitor; Protein Isoforms; Resistance; Role; Techniques; Therapeutic; Tumor Tissue; effective therapy; improved; inhibitor/antagonist; malignant breast neoplasm; mouse model; next generation sequencing; novel; pre-clinical; resistance mechanism; therapy resistant; translational clinical trial; treatment strategy

Although HER2-directed therapies are effective in the subset of breast cancers characterized by amplification of the HER2 gene (HER2+), resistance to these therapies remains an important clinical problem and the mechanisms of this resistance are not well defined. Recent data demonstrate that at least 40% of HER2+ breast cancers have activating mutations in the PI3-kinase gene (PIK3CA) or other alterations in the PI3K pathway. Furthermore, preclinical and clinical investigations, including our own, have implicated these PI3K pathway alterations as potential mediators of resistance to anti-HER2 therapy and have demonstrated that combining PI3K inhibitors with anti-HER2 agents can overcome this resistance. In Project 2, we aim to optimize the application of PI3K-directed therapies, both in novel genetically-engineered mouse (GEM) models and subsequently in a clinical trial. Since a combination of anti-HER2 therapy and PI3K inhibition will likely be ineffective for some patients due to additional mutations bypassing the HER2/PI3K pathway, we will utilize recently developed methods to study mechanisms of resistance that lie outside the PI3K pathway. The aims of this project are to identify and overcome both PI3K-dependent and -independent mechanisms of resistance to targeted therapy of HER2+ breast cancer. Specifically we will: 1) Use GEM models to optimize PI3K-targeted treatment strategies for each subset of HER2+ breast cancer, with an emphasis on comparing pan-PI3K inhibitors with isoform specific agents, 2) Identify novel resistance mechanisms to HER2- and PI3K-targeted therapies in GEM models, and 3) Evaluate the role of PI3K inhibition in conjunction with HER2-targeted therapy in a preoperative clinical trial of patients with HER2+ breast cancer. Tumor tissue from that trial and others will be analyzed with next generation sequencing techniques in order to validate resistance mechanisms identified in Aim 2. Together these studies will strengthen our ability to overcome therapeutic resistance in HER2+ breast cancer and thereby improve outcomes for patients with this disease.

尽管针对 HER2 的疗法对以 HER2 基因扩增 (HER2+) 为特征的乳腺癌亚型有效，但对这些疗法的耐药性仍然是一个重要的临床问题，并且这种耐药性的机制尚未明确。最近的数据表明，至少 40% 的 HER2+ 乳腺癌存在 PI3 激酶基因 (PIK3CA) 的激活突变或 PI3K 通路的其他改变。此外，包括我们自己在内的临床前和临床研究表明这些 PI3K 通路的改变是抗 HER2 治疗耐药的潜在介质，并证明将 PI3K 抑制剂与抗 HER2 药物相结合可以克服这种耐药性。在项目 2 中，我们的目标是优化 PI3K 导向疗法在新型基因工程小鼠 (GEM) 模型中以及随后在临床试验中的应用。由于绕过 HER2/PI3K 途径的其他突变，抗 HER2 疗法和 PI3K 抑制的组合可能对某些患者无效，因此我们将利用最近开发的方法来研究 PI3K 途径之外的耐药机制。该项目的目的是确定并克服 PI3K 依赖性和非依赖性 HER2+ 乳腺癌靶向治疗的耐药机制。具体来说，我们将：1) 使用 GEM 模型优化 HER2+ 乳腺癌每个亚型的 PI3K 靶向治疗策略，重点是将泛 PI3K 抑制剂与亚型特异性药物进行比较，2) 在 GEM 模型中识别 HER2 和 PI3K 靶向治疗的新耐药机制，以及 3) 评估 PI3K 抑制与 HER2 靶向治疗相结合的作用 在 HER2+ 乳腺癌患者的术前临床试验中。该试验和其他试验的肿瘤组织将使用下一代测序技术进行分析，以验证目标 2 中确定的耐药机制。这些研究将共同​​增强我们克服 HER2+ 乳腺癌治疗耐药性的能力，从而改善该疾病患者的预后。