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HER 2导向疗法在以HER 2基因扩增（HER 2+）为特征的乳腺癌亚组中是有效的，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HER 2+乳腺癌在PI 3-激酶基因（PIK 3CA）中存在激活突变或PI 3 K途径中的其他改变。此外，临床前和临床研究（包括我们自己的研究）表明，这些PI 3 K通路改变是抗HER 2治疗耐药的潜在介质，并证明PI 3 K抑制剂与抗HER 2药物联合使用可以克服这种耐药。在项目2中，我们的目标是优化PI 3 K导向疗法在新型基因工程小鼠（GEM）模型和随后的临床试验中的应用。由于抗HER 2治疗和PI 3 K抑制的组合可能对某些患者无效，因为额外的突变绕过了HER 2/PI 3 K通路，我们将利用最近开发的方法来研究PI 3 K通路以外的耐药机制。该项目的目的是确定和克服HER 2+乳腺癌靶向治疗耐药的PI 3 K依赖性和非依赖性机制。具体而言，我们将：1）使用GEM模型来优化针对HER 2+乳腺癌的每个子集的PI 3 K靶向治疗策略，重点是将泛PI 3 K抑制剂与亚型特异性药物进行比较，和3）在HER 2+乳腺癌患者的术前临床试验中评估PI 3 K抑制与HER 2靶向治疗联合的作用。将使用下一代测序技术分析来自该试验和其他试验的肿瘤组织，以验证目标2中确定的耐药机制。这些研究将加强我们克服HER 2+乳腺癌治疗耐药性的能力，从而改善患有这种疾病的患者的预后。