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HER2定向的疗法在以扩增Her2基因（HER2+）为特征的乳腺癌的子集中有效，但对这些疗法的耐药性仍然是一个重要的临床问题，并且这种抗性的机制尚未得到很好的定义。最近的数据表明，在PI3-激酶基因（PIK3CA）中至少有40％的HER2+乳腺癌具有激活突变或PI3K途径中的其他变化。此外，临床前和临床研究（包括我们自己的）已将这些PI3K途径改变牵涉到对抗HER2治疗的抗性的潜在介体，并证明将PI3K抑制剂与抗HER2药物相结合可以克服这种抵抗力。在项目2中，我们旨在优化新型的遗传工程小鼠（GEM）模型以及随后在临床试验中的新型遗传学小鼠（GEM）模型中的应用。由于抗HER2治疗和PI3K抑制作用的组合对于某些患者而言，由于绕过HER2/PI3K途径的其他突变，我们将利用最近开发的方法来研究PI3K途径以外的抗性机制。该项目的目的是识别和克服PI3K依赖性和非依赖性的对HER2+乳腺癌靶向治疗的抗性机制。 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通过下一代测序技术进行分析，以验证AIM 2中确定的抗药性机制。这些研究将增强我们在HER2+乳腺癌中克服治疗性抗性的能力，从而改善这种疾病患者的结局。