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: 10215415
• 负责人: Jean Zhao
• 金额: $ 30.51万
• 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/10215415
• 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/antagonist; 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.

项目概要 乳腺癌脑转移 (BCBM) 影响多达一半的晚期 HER2+ 乳腺癌患者，以及 10-15% 的患者。 晚期 ER+/HER2- 乳腺癌患者。标准护理包括手术和/或放射治疗；然而，这些 方法可能会产生严重的毒性，不能解决全身性疾病，并使患者面临感染的风险 未来中枢神经系统进展（CNS）和死亡。尽管具有临床影响，但现有的临床前模型 BCBM 受到限制，影响 BCBM 生长的因素尚未得到很好的阐明。迄今为止，还没有系统性的 治疗 BCBM 的疗法已获得监管部门的批准——因此，这代表了一个主要、持久和广泛的领域。 未满足的医疗需求。临床前研究，包括我们自己的研究，表明至少有两个关键途径发挥作用—— PI3K/PTEN/mTOR 和细胞周期蛋白 D1/CDK4 — 在 BCBM 的生长和维持中。该项目的总体目标 旨在阐明 PI3K/PTEN/mTOR 通路和 Cyclin D1/CDK4 通路在生长和发育中的作用 BCBM 的开发，剖析对这些途径抑制剂的位点特异性反应/耐药性的基础，测试 针对 BCBM 患者的通路的临床效用，并确定预测和克服治疗的方法 耐药性，长期目标是确定更有效的治疗和预防策略。为了完成我们的 为了实现这一目标，我们组建了一个多学科团队，使实验室和实验室之间能够进行密切的双向合作。 诊所。我们将利用由人类 BCBM 生成的独特的患者来源异种移植 (PDX) 模型集合 标本和基因工程小鼠模型 (GEMM)，与最先进的分子病理学相结合 技术。在目标 1 中，我们将 1）测试 PTEN 丢失是否促进 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PI3K/mTOR抑制剂 在 BCBM 的临床前模型中并揭示位点特异性耐药的潜在机制； 3）测试功效 HER2+ BCBM 患者联合 PI3K/mTOR 阻断。在目标 2 中，我们将 1) 评估 CDK4/6 的功效 单独和合理组合的抑制，2) 评估 CDK4/6 抑制剂的功效和免疫调节作用， 单独使用或与免疫检查点阻断相结合以及在不同的遗传背景下使用，以及 3) 探索临床 HER2 和 CDK4/6 联合抑制对 HER2+ BCBM 患者的疗效。总之，这些研究将进一步推动我们 了解 BCBM 的病理生理学，增强我们克服治疗耐药性的能力，并改善 患有这种疾病的患者的结果。