Improving treatment of brain metastases from HER2-positive breast cancer

改善 HER2 阳性乳腺癌脑转移的治疗

• 批准号: 8864389
• 负责人: Rakesh K. Jain
• 金额: $ 39.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8864389
• 关键词: Aftercare; Animal Model; Antibodies; Biological Markers; Brain; Brain Neoplasms; Breast; Breast Cancer Cell; Breast Cancer cell line; Cell Proliferation; Cell Survival; Cells; Cerebrum; Clinical; Clinical Trials; Combined Modality Therapy; Comparative Study; Development; Dimerization; Drug Targeting; ERBB2 gene; ERBB3 gene; Family member; Fatty acid glycerol esters; Future; Genetic Models; Growth; HER2 inhibition; Heterodimerization; Human; Imaging Techniques; Imaging technology; Implant; In Vitro; Inhibition of Apoptosis; Lesion; Ligands; MAP Kinase Gene; Mammary gland; Measures; Mediating; Metabolic; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Modeling; Molecular; Morbidity - disease rate; Mus; Neoplasm Metastasis; Neuregulin 1; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Primary Neoplasm; Production; Resistance; Resolution; Role; Signal Transduction; Site; Slice; Survival Rate; Systemic disease; Techniques; Testing; Therapeutic; Tissues; Transgenic Mice; Trastuzumab; attenuation; cancer cell; clinically relevant; combinatorial; design; effective therapy; efficacy testing; glucose uptake; human FRAP1 protein; human tissue; improved; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; meetings; mouse model; multidisciplinary; neoplastic cell; new therapeutic target; novel; outcome forecast; overexpression; palliative; preclinical study; public health relevance; research study; response; targeted treatment; translational study; treatment response; treatment strategy; tumor; tumor growth

 DESCRIPTION (provided by applicant): Treatment of cerebral metastases of HER2-positive (HER2+) breast cancer remains an unmet need. The development of novel HER2 targeting agents has revolutionized the treatment of HER2+ systemic disease; however, the efficacy of these targeted drugs is very limited in the brain microenvironment. Treatment is palliative in the majority of the cases, with survival rates varying between 4-12 months. This poor prognosis emphasizes the urgent need to unravel the mechanisms that underlie resistance of brain metastases (BM) to HER2 targeted drugs, in order to optimize therapeutic approaches in this setting. Recent preclinical studies indicate that ErbB3 (HER3) has a central role in promoting resistance to HER2 targeted therapies. We have discovered that HER3 and its activating ligand neuregulin-1 (NRG-1) are highly expressed in HER2+ breast cancer BM. Moreover, we have found that HER3 blockade enhances the efficacy of anti-HER2 therapy in the brain, resulting in significant tumor growth delay and improved survival. Building on these exciting preliminary findings, we now propose to unravel the mechanisms involved in HER3-mediated resistance to HER2 inhibition in the brain using well-characterized primary and patient-derived human HER2+ breast cancer cell lines, transgenic mouse models, and state-of-the-art imaging techniques. In Aim 1, we will examine the molecular mechanisms of NRG-1-dependent HER3 activation in the brain microenvironment. In Aim 2, we will investigate how the NRG-HER3 axis mediates resistance to anti-HER2 therapies. Lastly, in Aim 3 we will determine the effects of combinatorial NRG-1/HER3 and HER2 pathway inhibition in translational studies using brain metastasis models. To realize these aims, we have developed clinically relevant animal models of breast cancer BM, and powerful, non-invasive, high resolution imaging technologies that provide unprecedented molecular, cellular, structural and functional insights, and reveal various steps of BM progression. We will use these techniques and the unique collective expertise of our multidisciplinary team to uncover the role of the NRG-1/HER3 axis in mediating resistance to HER2 targeted therapies. Furthermore, we will validate the therapeutic benefit of combinatorial treatment strategies, which will directly inform clinical trials in patients with HER2+ breast cancr brain metastases, and will meet the urgent need for effective therapies.

 描述（由申请人提供）： HER2 阳性 (HER2+) 乳腺癌脑转移的治疗仍然是一个未满足的需求。新型 HER2 靶向药物的开发彻底改变了 HER2+ 全身性疾病的治疗；然而，这些靶向药物的疗效还很有限。大多数病例的治疗效果非常有限，生存率在 4-12 个月之间变化，这表明迫切需要解开其机制。最近的临床前研究表明，ErbB3 (HER3) 在促进 HER2 靶向药物耐药性方面发挥着核心作用。其激活配体神经调节蛋白-1 (NRG-1) 在 HER2+ 乳腺癌 BM 中高表达，此外，我们发现 HER3 阻断增强了疗效。基于这些令人兴奋的初步发现，我们现在建议使用充分表征的原发性和抗性来揭示大脑中 HER3 介导的对 HER2 抑制的抵抗力。患者来源的人 HER2+ 乳腺癌细胞系、转基因小鼠模型和最先进的成像技术在目标 1 中，我们将研究大脑微环境中 NRG-1 依赖性 HER3 激活的分子机制。目标 2，我们将研究 NRG-HER3 轴如何介导抗 HER2 疗法的耐药性。最后，在目标 3 中，我们将使用脑转移模型确定组合 NRG-1/HER3 和 HER2 通路抑制的效果。为了实现这些目标，我们开发了临床相关的乳腺癌 BM 动物模型，以及强大的、非侵入性的高分辨率成像技术，提供前所未有的分子、细胞、结构和功能见解，并揭示 BM 进展的各个步骤。我们将利用这些技术和我们多学科团队独特的集体专业知识来揭示 NRG-1/HER3 轴在介导 HER2 靶向治疗耐药性中的作用。此外，我们将验证组合治疗策略的治疗益处，这将直接影响治疗效果。为 HER2+ 乳腺癌脑转移患者的临床试验提供信息，并将满足对有效治疗的迫切需求。