Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer

项目总结 Dana-Farber/哈佛癌症中心(DF/HCC)在乳腺癌中的孢子寻求改善 使用创新和高度翻译的方法来理解和治疗乳腺癌。这个 应用程序包括四个项目、三个核心、一个发展研究方案(DRP)和一个职业 增强计划(CEP)。每个项目都解决了一个根本性的挑战，这会导致过早 死亡率或严重发病率。项目1召集了优秀的研究人员来研究 对CDK4/6抑制剂的耐药性。在雌激素受体阳性的乳腺癌中，我们假设CDK2 过度激活是对CDK4/6抑制剂产生获得性耐药的原因之一。优雅的临床前工作将是 补充了一项临床研究，其中在启动CDK4/6抑制剂之前进行了成对的活检 当抵抗力发展时。在三阴性乳腺癌中，我们将评估溶酶体 CDK4/6抑制剂的隔离限制了它们的治疗效果。在临床前工作中，我们将确定这是否 使用氯喹可以逆转隔离，还将进行帕博西利/氯喹的试验 在RB完整的三阴性疾病中。项目2使用两个“联合临床”试验--运行随机人体试验 和小鼠实验很大程度上是平行的-研究两种新的治疗方法来增强抗 对HER2阳性乳腺癌的肿瘤免疫应答(CDK4/6抑制和双重PDL1和4-1BB 目标)。这两种方法都基于我们令人信服的临床前数据，并将包括本地和国际 合作者。项目3解决了乳腺癌脑转移的挑战。利用我们独一无二的 人脑转移瘤切除后异种移植物的收集和脑传导的经验 在肿瘤转移特异性试验中，我们将测试两种新的系统治疗方案的生物学和临床影响。 项目4的重点是三阴性乳腺癌。我们将进行全面的临床前研究和 临床试验，以确定靶向治疗是否可以使三阴性肿瘤对免疫治疗敏感。我们 将评估PARP抑制剂或BET溴域抑制剂与免疫检查点的组合 封锁。核心A是行政核心，是科学、财政和行政监督的中心。它 将领导规划和沟通的努力，并设有患者倡导委员会。核心A将 确保现有的DF/HCC结构支持孢子临床研究工作。核心B，生物统计学 和计算生物学核心，提供生物统计和基因组管理方面的专业知识 数据。核心C，生物学家和病理学核心，将维护孢子的组织/血液储存库 项目和孢子外的调查人员。它还为项目提供关键的病理服务 并将进行尖端分析。核心C还包括免疫肿瘤子核心。DRP和CEP 找出乳腺癌翻译问题的新方法，并支持年轻的研究人员。我们的 乳腺癌中的孢子将在未来五年及以后做出重大贡献。

PROJECT SUMMARY The Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE in Breast Cancer seeks to improve the understanding and treatment of breast cancer using an innovative and highly translational approach. The application consists of four projects, three cores, a developmental research program (DRP) and a career enhancement programs (CEP). Each project addresses a fundamental challenge that results in premature mortality or substantial morbidity. Project 1 brings together outstanding investigators to study mechanisms of resistance to CDK4/6 inhibitors. In estrogen receptor-positive breast cancer, we hypothesize that CDK2 hyperactivation is a cause of acquired resistance to CDK4/6 inhibitors. Elegant preclinical work will be complemented by a clinical study in which paired biopsies are obtained prior to initiation of CDK4/6 inhibitors and when resistance develops. In triple-negative breast cancer, we will evaluate the possibility that lysosomal sequestration of CDK4/6 inhibitors limits their therapeutic efficacy. In preclinical work, we will determine if this sequestration can be reversed administering chloroquine and will also conduct a trial of palbociclib/chloroquine in RB-intact triple-negative disease. Project 2 uses two “co-clinical” trials – running randomized human trials and mouse experiments largely in parallel – to study two novel therapeutic approaches to enhance the anti- tumor immune response against HER2-positive breast cancers (CDK4/6 inhibition and dual PDL1 and 4-1BB targeting). Both approaches are based on our compelling preclinical data, and will include local and international collaborators. Project 3 tackles the challenge of breast cancer brain metastases. Leveraging our unique collection of xenografts derived from resected human brain metastases, and our experience conducting brain metastasis-specific trials, we will test the biologic and clinical impact of two novel systemic therapy regimens. Project 4 is focused on triple-negative breast cancer. We will perform comprehensive preclinical studies and clinical trials to determine whether targeted therapies can sensitize triple-negative tumors to immunotherapy. We will evaluate combinations of either PARP inhibitors or BET bromodomain inhibitors with immune checkpoint blockade. Core A, the Administrative Core, is the epicenter of scientific, fiscal and administrative oversight. It will lead efforts in planning and communication, and also houses the Patient Advocacy Committee. Core A will ensure that existing DF/HCC structures support the SPORE clinical research efforts. Core B, the Biostatistics and Computational Biology core, provides specialized expertise in biostatistics and management of genomic data. Core C, the Biospecimen and Pathology Core, will maintain tissue/blood repositories for the SPORE projects and for investigators outside of the SPORE. It also provides critical pathology services for the projects and will perform cutting edge assays. Core C also houses the Immuno-Oncology Sub Core. The DRP and CEP identify novel approaches to translational questions in breast cancer and support young investigators. Our SPORE in Breast Cancer is poised to make substantial contributions over the next five years and beyond.