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

基本信息

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
项目类别：
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

项目摘要

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- 乳腺癌患者的标准护理包括手术和/或放射治疗；然而，方法可能与显着的毒性相关，不能解决全身性疾病，并使患者面临风险尽管存在临床影响，但现有的临床前模型仍然存在未来中枢神经系统进展（CNS）和死亡的风险。 BCBM 的研究有限，而且影响 BCBM 生长的因素至今尚未得到很好的阐明。该疗法已获得监管部门批准用于治疗 BCBM——因此，这代表了一个重大、持久和广泛的领域。未满足的医疗需求，包括我们自己的临床前研究表明，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抵抗，长期目标是确定更有效的治疗和预防策略，以实现我们的目标。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性的潜在机制；3）测试其功效；联合 PI3K/mTOR 阻断治疗 HER2+ BCBM 患者在目标 2 中，我们将 1) 评估 CDK4/6 的疗效。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进我们的研究。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。