Project 3: Improving therapeutic approaches for breast cancer brain metastases

项目摘要 乳腺癌脑转移（BCBM）影响多达一半的晚期HER 2+乳腺癌患者和10-15%的 晚期ER+/HER 2-乳腺癌患者。标准治疗包括手术和/或放射治疗;然而， 这些方法可能与实质性毒性相关，不能解决全身性疾病，并使患者面临以下风险： 未来中枢神经系统进展（CNS）和死亡。尽管它们的临床影响，现有的临床前模型， BCBM的生长受到限制，影响BCBM生长的因素还没有很好地阐明。到目前为止，没有系统的 治疗BCBM已获得监管批准，因此这代表了一个主要的，持久的， 未满足的医疗需求包括我们自己在内的临床前研究表明，至少有两个关键途径发挥作用- PI 3 K/PTEN/mTOR和cyclin D1/CDK 4-在BCBM生长和维持中的作用。本项目的总体目标是 阐明PI 3 K/PTEN/mTOR通路和Cyclin D1/CDK 4通路在细胞生长和增殖中的作用， BCBM的开发，剖析这些途径抑制剂的位点特异性反应/抗性的基础，测试 在BCBM患者中靶向通路的临床效用，并确定预测和克服治疗性疾病的方法。 长期目标是确定更有效的治疗和预防战略。完成我们 为了实现这一目标，我们组建了一个多学科团队，使实验室和 诊所我们将利用我们独特的从人BCBM生成的患者源性异种移植物（PDX）模型 标本和基因工程小鼠模型（GEMM），结合最先进的分子病理学 技术.在目标1中，我们将1）测试PTEN缺失是否促进BCBM的生长和维持，并评估 PTEN表达的遗传或药理学恢复的影响; 2）评估脑渗透性PI 3 K/mTOR抑制剂 在BCBM的临床前模型中，并揭示位点特异性抗性的潜在机制;以及3）测试 在HER 2 + BCBM患者中联合PI 3 K/mTOR阻断。在目标2中，我们将1）评估CDK 4/6的疗效 单独和合理组合的抑制，2）评价CDK 4/6抑制剂的功效和免疫调节作用， 单独和与免疫检查点阻断组合以及在不同的遗传背景中，以及3）探索临床 HER 2和CDK 4/6联合抑制在HER 2 + BCBM患者中的疗效。这些研究将进一步推动我们的 了解BCBM的病理生理学，加强我们克服治疗阻力的能力， 对于患有这种疾病的患者来说。

Project Summary Breast cancer brain metastases (BCBM) affect up to half of patients with advanced HER2+ breast cancer and 10-15% of patients with advanced ER+/HER2- breast cancer. Standard of care includes surgery and/or radiotherapy; however, these approaches can be associated with substantial toxicities, do not address systemic disease, and leave patients at risk for future central nervous system progression (CNS) and death. Despite their clinical impact, existing preclinical models of BCBM have been limited, and the factors which influence BCBM growth are not well elucidated. To date, no systemic therapy has gained regulatory approval for the treatment of BCBM—hence this represents an area of major, persistent, and unmet medical need. Preclinical investigations, including our own, have suggested a role for at least two key pathways— PI3K/PTEN/mTOR and cyclin D1/CDK4—in the growth and maintenance of BCBM. The overarching goals of this project are to elucidate the roles of the PI3K/PTEN/mTOR pathway and the Cyclin D1/CDK4 pathway in the growth and development of BCBM, to dissect the basis of site-specific response/resistance to inhibitors of these pathways, to test the clinical utility of targeting the pathways in patients with BCBM, and to identify ways to predict and overcome therapeutic resistance, with the long-term goal of identifying more effective treatment and prevention strategies. To accomplish our aims, we have assembled a multidisciplinary team enabling close bi-directional collaboration between the laboratory and clinic. We will leverage our unique collection of patient-derived xenograft (PDX) models generated from human BCBM specimens, and genetically-engineered mouse models (GEMMs), married with state-of-the art molecular pathology techniques. In Aim 1, we will 1) test whether PTEN loss promotes the growth and maintenance of BCBMs, and evaluate the effects of genetic or pharmacologic restoration of PTEN expression; 2) evaluate brain-penetrant PI3K/mTOR inhibitors in preclinical models of BCBM and uncover potential mechanisms of site-specific resistance; and 3) test the efficacy of combined PI3K/mTOR blockade in patients with HER2+ BCBM. In Aim 2, we will 1) evaluate the efficacy of CDK4/6 inhibition, alone and in rational combinations, 2) evaluate the efficacy and immuno-modulatory effects of CDK4/6 inhibitors, alone and in combination with immune checkpoint blockade and in varying genetic backgrounds, and 3) explore the clinical efficacy of combined HER2 and CDK4/6 inhibition in patients with HER2+ BCBM. Together, these studies will further our understanding of the pathophysiology of BCBM, strengthen our ability to overcome therapeutic resistance, and improve outcomes for patients with this disease.