Project 3: Improving therapeutic approaches for breast cancer brain metastases

项目3：改进乳腺癌脑转移的治疗方法

• 批准号: 10455692
• 负责人: Jean Zhao
• 金额: $ 26.36万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455692
• 关键词: Affect; Area; Brain; Breast Cancer Model; Breast Cancer Treatment; CDK4 gene; Cancer Center; Cell Cycle; Cessation of life; Clinic; Clinical; Collaborations; Collection; Cyclin D1; Data; Disease; ERBB2 gene; Estrogen Receptors; FDA approved; FRAP1 gene; Functional disorder; Future; Genetic; Genetically Engineered Mouse; Goals; Growth; Growth and Development function; Human; Immune; Immune checkpoint inhibitor; Investigation; Laboratories; Maintenance; Mediating; Medical; Metastatic malignant neoplasm to brain; Morbidity - disease rate; Neuraxis; Operative Surgical Procedures; PTEN gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Play; Pre-Clinical Model; Prevention strategy; Radiation therapy; Resistance; Risk; Role; Site; Source; Specimen; Systemic Therapy; Systemic disease; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Toxic effect; cancer subtypes; clinical efficacy; effective therapy; efficacy evaluation; efficacy testing; immune checkpoint blockade; immunoregulation; improved; improved outcome; inhibitor; mTOR Inhibitor; malignant breast neoplasm; molecular pathology; mortality; multidisciplinary; novel therapeutic intervention; patient derived xenograft model; pre-clinical; response; restoration; standard of care; targeted treatment; therapeutically effective; therapy resistant; treatment strategy

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.

项目摘要 乳腺癌脑转移（BCBM）影响多达一半的晚期HER2+乳腺癌患者，10-15％ 晚期ER+/HER2-乳腺癌患者。护理标准包括手术和/或放疗；但是，这些 方法可能与实质性毒性有关，不解决全身性疾病，并使患者处于风险 未来的中枢神经系统进展（CNS）和死亡。尽管它们的临床影响，但现有的临床前模型 BCBM受到限制，影响BCBM增长的因素没有很好地阐明。迄今为止，没有系统 治疗已获得治疗BCBM的监管部门批准，因此，这代表了主要，持久和 未满足的医疗需求。包括我们自己在内的临床前研究提出了至少两个关键途径的作用 - PI3K/PTEN/MTOR和细胞周期蛋白D1/CDK4 - 在BCBM的生长和维护中。该项目的总体目标 阐明PI3K/PTEN/MTOR途径和细胞周期蛋白D1/CDK4途径在生长和 开发BCBM，以剖析对这些途径抑制剂特异性反应/抗性的基础，以测试 靶向BCBM患者的途径的临床实用性，并确定预测和克服治疗的方法 抵抗，其长期目标是确定更有效的治疗和预防策略。完成我们的 目的，我们组建了一个多学科团队，实现了实验室与 诊所。我们将利用人类BCBM生成的独特的患者衍生Xenographotic（PDX）模型集合 标本和遗传工程的小鼠模型（GEMMS）已婚 技术。在AIM 1中，我们将1）测试PTEN损失是否促进BCBM的增长和维护，并评估 PTEN表达的遗传或药物恢复的影响； 2）评估脑穿透剂PI3K/mTOR抑制剂 在BCBM的临床前模型中，并发现了位点特异性电阻的潜在机制； 3）测试效率 HER2+ BCBM患者的PI3K/MTOR阻断合并。在AIM 2中，我们将1）评估CDK4/6的效率 抑制，单独和合理组合，2）评估CDK4/6抑制剂的有效性和免疫调节作用， 单独并结合免疫切除点封锁和不同的遗传背景，3）探索临床 HER2和CDK4/6联合抑制在HER2+ BCBM患者中的功效。这些研究将共同​​进一步 了解BCBM的病理生理学，增强我们克服治疗抗性的能力，并提高 这种疾病患者的结果。