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

• 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
• 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

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 丹娜-法伯/哈佛癌症中心（DF/HCC）乳腺癌SPORE旨在改善 使用创新和高度转化的方法来理解和治疗乳腺癌。的 申请包括四个项目，三个核心，发展研究计划（DRP）和职业生涯 增强计划（CEP）。每个项目都解决了一个根本性的挑战， 死亡或严重发病。项目1汇集了杰出的研究人员，研究 对CDK 4/6抑制剂的耐药性。在雌激素受体阳性乳腺癌中，我们假设CDK 2 超活化是对CDK 4/6抑制剂获得性抗性的原因。优雅的临床前工作将是 辅以临床研究，其中在开始使用CDK 4/6抑制剂之前获得配对活检 以及何时出现抗药性。在三阴性乳腺癌中，我们将评估溶酶体 CDK 4/6抑制剂的隔离限制了它们的治疗功效。在临床前工作中，我们将确定 使用氯喹可以逆转隔离，还将进行palbociclib/氯喹试验 在RB完整的三阴性疾病中。项目2使用了两个“联合临床”试验--进行随机人体试验 和小鼠实验在很大程度上平行-研究两种新的治疗方法，以提高抗- 针对HER 2阳性乳腺癌的肿瘤免疫应答（CDK 4/6抑制和双重PDL 1和4-1BB 瞄准）。这两种方法都是基于我们令人信服的临床前数据，并将包括当地和国际 合作者项目3应对乳腺癌脑转移的挑战。利用我们独特的 收集来自切除的人脑转移瘤的异种移植物，以及我们进行脑转移瘤治疗的经验。 转移特异性试验，我们将测试两种新的全身治疗方案的生物学和临床影响。 项目4关注三阴性乳腺癌。我们将进行全面的临床前研究， 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布罗莫结构域抑制剂与免疫检查点的组合 封锁核心A，即行政核心，是科学、财政和行政监督的中心。它 将在规划和沟通方面发挥主导作用，并设有患者倡导委员会。核心A将 确保现有DF/HCC结构支持SPORE临床研究工作。核心B，生物统计学 和计算生物学核心，提供生物统计学和基因组管理方面的专业知识， 数据核心C，即生物标本和病理学核心，将维护SPORE的组织/血液储存库 项目和调查人员以外的孢子。它还为项目提供关键病理学服务 并将进行尖端检测核心C还包含免疫肿瘤学子核心。DRP和CEP 确定乳腺癌转化问题的新方法，并支持年轻的研究人员。我们 乳腺癌的孢子准备在未来五年及以后做出重大贡献。

项目成果

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

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

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
• 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