ANALYSIS AND THERAPEUTIC TARGETING OF BREAST CANCER DISSEMINATED TUMOR CELLS

乳腺癌播散性肿瘤细胞的分析和治疗靶向

• 批准号: 9318459
• 负责人: Rebecca L. Aft
• 金额: $ 38.48万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318459
• 关键词: Address; Aspirate substance; Behavior; Biological; Biological Assay; Biological Markers; Bone Marrow; Breast Cancer Cell; Breast Cancer Patient; Breast cancer metastasis; Cells; Chemotherapy-Oncologic Procedure; Classification; Clinical; Clinical Trials; Data; Detection; Development; Disease; Disease-Free Survival; Distant; ERBB2 gene; Effectiveness; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Goals; Interruption; Intervention; Metastatic to; Micrometastasis; Molecular; Molecular Profiling; Monitor; Neoplasm Metastasis; Pathway interactions; Patients; Phase; Phenotype; Primary Neoplasm; Randomized Clinical Trials; Recurrence; Regulator Genes; Resistance; Science; Specimen; Staining method; Stains; Structural Genes; Therapeutic; Time; Trastuzumab; base; biomarker identification; cancer recurrence; cancer subtypes; chemotherapy; clinical practice; cohort; follow-up; gene panel; malignant breast neoplasm; metastatic process; molecular marker; molecular subtypes; mortality; nano-string; neoplastic cell; patient subsets; predictive marker; prognostic; prospective; public health relevance; randomized trial; response; targeted treatment; therapeutic target; tumor

DESCRIPTION (provided by applicant): Metastasis is the most significant contributor to mortality in breast cancer patients. In breast cancer patients, bone marrow (BM) is thought to serve as a reservoir for disseminated tumor cells (DTCs), which are the hypothesized intermediaries in the metastatic process. Our goal is to molecularly classify DTCs for predictive biomarker identification and therapeutic targeting. We have developed a strategy for identifying genes associated with DTCs and a multiple assay, Nanostring nCounter for their analysis. We hypothesize that introducing a validated set of molecular markers for the detection and molecular classification of DTCs into clinical practice for the implementation of targeted therapies will result in a halting of metastatic disease development by interrupting the metastatic cascade. Our goals are to refine and validate a 46-gene expression profile for the detection and classification of DTCs using BM specimens from a 120 patient cohort of clinical stage II/III breast cancer patients and to conduct a phase II randomized trial evaluating the effect of trastuzumab on the elimination of ERRB2-positive disseminated tumor cells and DFS in early stage Her2-negative primary breast cancer patients with ERBB2 expressing BM DTCs. Our proposal will provide proof of principle that we can identify subsets of patients who will respond to specific targeted therapies based on the predictive biomarker expression profile of their DTCs and that eliminating DTCs results in a DFS benefit. This project will result in paradigm shift for treating early stage breast cancer patients based on the DTC predictive biomarker expression profile.

描述（由申请人提供）：转移是乳腺癌患者死亡率的最重要因素。在乳腺癌患者中，骨髓（BM）被认为是播散性肿瘤细胞（DTC）的储存库，这些细胞是转移过程中的假设中介。我们的目标是对DTC进行分子分类，用于预测性生物标志物鉴定和治疗靶向。我们已经开发了一种用于识别与DTC相关的基因的策略，以及用于其分析的多重测定Nanostring nCounter。我们假设，将一组经过验证的用于DTC检测和分子分类的分子标记物引入临床实践以实施靶向治疗，将通过中断转移性肿瘤来阻止转移性疾病的发展。 级联。我们的目标是使用来自120名临床II/III期乳腺癌患者的BM标本来完善和验证用于DTC检测和分类的46个基因表达谱，并进行II期随机试验，以评估曲妥珠单抗对消除ERRB 2阳性播散性肿瘤细胞和早期Her 2 - 3患者DFS的影响。ERBB 2表达BM DTC的阴性原发性乳腺癌患者。我们的提案将提供原则性证据，证明我们可以根据DTC的预测性生物标志物表达谱确定对特定靶向治疗有反应的患者子集，并且消除DTC会带来DFS获益。该项目将导致基于DTC预测生物标志物表达谱治疗早期乳腺癌患者的范式转变。

项目成果

Paired-like Homeodomain Transcription factor 2 expression by breast cancer bone marrow disseminated tumor cells is associated with early recurrent disease development.

• DOI: 10.1007/s10549-015-3576-z
• 发表时间: 2015-10
• 期刊: Breast cancer research and treatment
• 影响因子: 3.8
• 作者: Pillai SG;Dasgupta N;Siddappa CM;Watson MA;Fleming T;Trinkaus K;Aft R
• 通讯作者: Aft R

Identifying biomarkers of breast cancer micrometastatic disease in bone marrow using a patient-derived xenograft mouse model.

• DOI: 10.1186/s13058-017-0927-1
• 发表时间: 2018-01-02
• 期刊: Breast cancer research : BCR
• 作者: Pillai SG;Li S;Siddappa CM;Ellis MJ;Watson MA;Aft R
• 通讯作者: Aft R

Enrichment and Molecular Analysis of Breast Cancer Disseminated Tumor Cells from Bone Marrow Using Microfiltration.

乳腺癌的富集和分子分析使用微滤从骨髓中传播了肿瘤细胞。

• DOI: 10.1371/journal.pone.0170761
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Pillai SG;Zhu P;Siddappa CM;Adams DL;Li S;Makarova OV;Amstutz P;Nunley R;Tang CM;Watson MA;Aft RL
• 通讯作者: Aft RL