Improving treatment of brain metastases from HER2-positive breast cancer

 描述（由申请方提供）：HER 2阳性（HER 2+）乳腺癌脑转移的治疗仍然是一个未满足的需求。新型HER 2靶向药物的开发彻底改变了HER 2+系统性疾病的治疗;然而，这些靶向药物在脑微环境中的疗效非常有限。在大多数情况下，治疗是姑息性的，生存率在4-12个月之间。这种不良预后强调迫切需要解开脑转移瘤（BM）对HER 2靶向药物耐药的机制，以优化这种情况下的治疗方法。最近的临床前研究表明，ErbB 3（HER 3）在促进对HER 2靶向治疗的耐药性方面具有核心作用。我们已经发现，HER 3及其活化配体神经调节蛋白-1（NRG-1）在HER 2+乳腺癌BM中高度表达。此外，我们发现HER 3阻断增强了抗HER 2治疗在脑中的功效，导致显著的肿瘤生长延迟和生存期改善。基于这些令人兴奋的初步研究结果，我们现在建议使用充分表征的原发性和患者来源的人HER 2+乳腺癌细胞系，转基因小鼠模型和最先进的成像技术来阐明脑中HER 3介导的对HER 2抑制的耐药机制。在目标1中，我们将研究脑微环境中NRG-1依赖性HER 3激活的分子机制。在目标2中，我们将研究NRG-HER 3轴如何介导抗HER 2治疗的耐药性。最后，在目标3中，我们将使用脑转移模型确定组合NRG-1/HER 3和HER 2途径抑制在翻译研究中的作用。为了实现这些目标，我们开发了乳腺癌BM的临床相关动物模型，以及强大的非侵入性高分辨率成像技术，这些技术提供了前所未有的分子，细胞，结构和功能见解，并揭示了BM进展的各个步骤。我们将使用这些技术和我们多学科团队的独特集体专业知识来揭示NRG-1/HER 3轴在介导对HER 2靶向治疗的耐药性中的作用。此外，我们将验证组合治疗策略的治疗益处，这将直接为HER 2+乳腺癌脑转移患者的临床试验提供信息，并将满足对有效疗法的迫切需求。

 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.