Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer

丹娜—法伯癌症研究所/哈佛大学癌症中心 SPORE 在乳腺癌中的应用

基本信息

批准号：
10668334
负责人：
NANCY U LIN
金额：
$ 230.22万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668334
关键词：
Address Award Biological Biological Assay Biological Testing Biology Biometry Biopsy Blood Breast Cancer Treatment Breast Cancer therapy Bromodomain Bromodomains and extra-terminal domain inhibitor CDK2 gene CDK4 gene Cancer Biology Cancer Center Cancer Patient Chloroquine Clinic Clinical Clinical Data Clinical Investigator Clinical Research Clinical Trials Clinical Trials Cooperative Group Collaborations Collection Combined Modality Therapy Communication Complement Computational Biology Dana-Farber Cancer Institute Data Development Disease ERBB2 gene Ensure Estrogen receptor positive Funding Future General Hospitals Goals Growth Hospitals Human Immune Evasion Immune system Immunology Immunooncology Immunotherapy Individual Institution International Investigation Israel Laboratories Laboratory Research Lead Learning Massachusetts Medical center Mentors Metastatic Neoplasm to the Central Nervous System Metastatic malignant neoplasm to brain Methods Morbidity - disease rate Mus Neoplasm Metastasis Pathology Pathway interactions Patient advocacy Patients Poly(ADP-ribose) Polymerase Inhibitor Pre-Clinical Model Premature Mortality Randomized Regimen Reproduction spores Research Research Personnel Research Project Grants Resected Resistance Resistance development Resources Role Running Services Site Structure Systemic Therapy Testing Tissues Translating Translational Research Treatment Efficacy Woman Work Xenograft procedure anti-tumor immune response biomarker discovery cancer immunotherapy cancer subtypes career co-clinical trial experience experimental study genomic data immune checkpoint blockade improved inhibitor innovation insight malignant breast neoplasm molecular subtypes next generation novel novel strategies novel therapeutic intervention patient population pharmacologic pre-clinical preclinical study programmed cell death ligand 1 programs repository resistance mechanism symposium targeted treatment therapy resistant translational approach translational impact translational scientist triple-negative invasive breast carcinoma tumor tumor immunology tumor-immune system interactions

项目摘要

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.

项目摘要乳腺癌中的Dana-Farber/Harvard Cancer Center（DF/HCC）孢子试图改善使用一种创新且高度翻译的方法来理解和治疗乳腺癌。这申请包括四个项目，三个核心，一个发展研究计划（DRP）和职业增强程序（CEP）。每个项目都应对导致过早的基本挑战死亡率或大量发病率。项目1汇集了杰出的研究人员来研究对CDK4/6抑制剂的抗性。在雌激素受体阳性乳腺癌中，我们假设CDK2 过度激活是对CDK4/6抑制剂的抗性的原因。优雅的临床前工作将是通过临床研究完成，在启动CDK4/6抑制剂之前，获得了配对的活检当阻力发展时。在三阴性乳腺癌中，我们将评估溶酶体的可能性 CDK4/6抑制剂的固结限制了其治疗效率。在临床前工作中，我们将确定是否可以逆转静止的氯喹，还将进行palbociclib/chloroquine的试验在RB-Intact三阴性疾病中。项目2使用两个“共同链接”试验 - 进行随机人类试验和小鼠实验主要是同时进行的 - 研究两种新型的治疗方法，以增强抗 - 针对HER2阳性乳腺癌的肿瘤免疫反应（CDK4/6抑制作用和双PDL1和4-1BB 定位）。两种方法均基于我们引人注目的临床前数据，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。利用我们的独特之处收集了从切除的人脑转移衍生出的异种移植物，以及我们指导大脑的经验转移特异性试验，我们将测试两种新型全身疗法方案的生物学和临床影响。项目4专注于三阴性乳腺癌。我们将进行全面的临床前研究临床试验确定靶向疗法是否可以将三阴性肿瘤感知到免疫疗法。我们将评估具有免疫检查点的PARP抑制剂或BET溴结构域抑制剂的组合封锁。行政核心核心A核心是科学，财政和行政监督的中心。它将领导计划和沟通方面的努力，并在患者倡导委员会中任职。核心遗嘱确保现有的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，提供了基因组生物统计学和管理方面的专业专业知识数据。核心C，生物晶体和病理核心将维持孢子的组织/血液存储库项目和孢子以外的调查人员。它还为项目提供关键的病理服务并将执行前沿测定法。 Core C还容纳了免疫肿瘤的子核心。 DRP和CEP 确定乳腺癌中翻译问题的新方法并支持年轻研究者。我们的在未来五年及以后，乳腺癌中的孢子被毒死了，可以做出重大贡献。

项目成果

期刊论文数量（35）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identifying ERBB2 Activating Mutations in HER2-Negative Breast Cancer: Clinical Impact of Institute-Wide Genomic Testing and Enrollment in Matched Therapy Trials.

DOI：
10.1200/po.19.00087
发表时间：
2019-01-01
期刊：
JCO precision oncology
影响因子：
4.6
作者：
Exman, Pedro;Garrido-Castro, Ana C;Lin, Nancy U
通讯作者：
Lin, Nancy U

CDK4/6 Inhibition in Breast Cancer: Mechanisms of Response and Treatment Failure.

DOI：
10.1007/s12609-017-0232-0
发表时间：
2017-03
期刊：
Current breast cancer reports
影响因子：
0.9
作者：
Garrido-Castro AC;Goel S
通讯作者：
Goel S

Rates of pathologic nodal disease among cN0 and cN1 patients undergoing routine axillary ultrasound and neoadjuvant chemotherapy.

接受常规腋窝超声和新辅助化疗的 cN0 和 cN1 患者的病理性淋巴结疾病发生率。

DOI：
10.1007/s10549-022-06677-2
发表时间：
2022
期刊：
Breast cancer research and treatment
影响因子：
3.8
作者：
Weiss,Anna;King,Claire;Vincuilla,Julie;Parker,Tonia;Portnow,Leah;Nakhlis,Faina;Dominici,Laura;Mittendorf,ElizabethA;King,TariA
通讯作者：
King,TariA

Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer.

DOI：
10.1186/s13058-022-01510-6
发表时间：
2022-03-05
期刊：
Breast cancer research : BCR
影响因子：
0
作者：
Watt AC;Goel S
通讯作者：
Goel S

HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.

DOI：
10.1038/nm.4292
发表时间：
2017-04
期刊：
Nature medicine
影响因子：
82.9
作者：
Davies H;Glodzik D;Morganella S;Yates LR;Staaf J;Zou X;Ramakrishna M;Martin S;Boyault S;Sieuwerts AM;Simpson PT;King TA;Raine K;Eyfjord JE;Kong G;Borg Å;Birney E;Stunnenberg HG;van de Vijver MJ;Børresen-Dale AL;Martens JW;Span PN;Lakhani SR;Vincent-Salomon A;Sotiriou C;Tutt A;Thompson AM;Van Laere S;Richardson AL;Viari A;Campbell PJ;Stratton MR;Nik-Zainal S
通讯作者：
Nik-Zainal S