Investigating mechanisms of chemoresistance in triple-negative breast cancer

研究三阴性乳腺癌的化疗耐药机制

• 批准号: 10549343
• 负责人: Madeleine Julie Oudin
• 金额: $ 34.01万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-11 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549343
• 关键词: Adipocytes; Adjuvant Chemotherapy; Affect; Aftercare; Automobile Driving; Breast Cancer Cell; Breast Cancer Patient; Cancer Burden; Caspase; Cathepsins B; Cell secretion; Cessation of life; Chemoresistance; Clinical; Collagen; Collagen Type IV; Crosslinker; Data; Development; Drug resistance; Endothelial Cells; Environment; Excision; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibronectins; Gene Expression Profile; Glycoproteins; Goals; Human; In Vitro; Individual; Invaded; Laminin; Macrophage; Malignant Neoplasms; Mammary Neoplasms; Metastasis Induction; Metastatic/Recurrent; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Paclitaxel; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Play; Population; Process; Property; Proteins; Proteoglycan; Recurrence; Relapse; Research; Residual Cancers; Resistance; Role; Sampling; Signal Transduction; Structural Protein; Structure; Testing; Therapeutic; Tissues; Tumor Tissue; Up-Regulation; cell motility; cell type; chemotherapy; improved; in vivo; insight; malignant breast neoplasm; neoplastic cell; novel; prevent; response; standard of care; therapy outcome; three-dimensional modeling; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression

Project Summary Chemotherapy remains the standard of care for patients with triple-negative breast cancer (TNBC), which affects 20% of patients with breast cancer. However, 50% of patients with localized TNBC treated with neoadjuvant chemotherapy display residual cancer burden after treatment and up to 25% of patients who receive this treatment will suffer metastatic recurrence within five years. The poor association between chemotherapy and patient outcome emphasizes two major problems for TNBC patients: chemoresistance, where tumor cells within the local environment are protected and do not die in response to chemotherapy, and chemotherapy-induced metastasis, where chemotherapy-induced changes in tumor intrinsic properties and the tumor microenvironment drive invasion which leads to recurrence. Previous studies have demonstrated that cell migration and extracellular matrix (ECM) remodeling are associated with chemoresistant TNBC. The goal of this proposal is to understand the mechanisms by which the ECM contributes to chemoresistance and chemotherapy-induced metastasis in TNBC. We provide preliminary data that individual proteins upregulated in TNBC tumors drive resistance to chemotherapy drug Paclitaxel and that expression of Cathepsin B (CTSB), a protease which degrades these ECM proteins into small fragments, protects against the development of chemoresistance. We will dissect the mechanism by which the protease CTSB and the ECM proteins it degrades influence response to Paclitaxel in TNBC and whether these fragments can be used to track and target chemoresistance in vivo. We have also found that chemotherapy treatment leads to changes in the ECM composition of mammary tumors. Specifically, Paclitaxel treatment leads to an increased abundance of Collagen IV, an ECM protein which promote invasion and metastasis in TNBC. Our goal is to determine the cell types that secrete ECM proteins such as Collagen IV after chemotherapy treatment, determine the contribution of these ECM proteins to chemotherapy-induced metastasis, and whether these pathways can be targeted to prevent the development of recurrence. Upon successful completion of the proposed research, our contribution is expected to be an understanding of how ECM proteins upregulated in TNBC tumors contribute to chemoresistance and how chemotherapy alters the ECM to promote recurrence and metastatic dissemination. These contributions will be significant because all TNBC patients receive chemotherapy and metastatic recurrence is a current unmet clinical need. Results from these studies will provide novel conceptual insights on mechanisms of chemoresistance and chemotherapy-induced metastasis and will allow us to develop new strategies to track, predict and overcome chemoresistance in TNBC.

项目摘要 化学疗法仍然是三阴性乳腺癌（TNBC）患者的护理标准，该患者 影响20％的乳腺癌患者。但是，有50％的局部TNBC患者接受治疗 新辅助化疗在治疗后显示残留的癌症负担，多达25％的患者 接受这种治疗将在五年内遭受转移性复发。之间不良的关联 化学疗法和患者结果强调了TNBC患者的两个主要问题：化学疗法， 局部环境中肿瘤细胞受到保护，并且不会因化学疗法而死亡，而 化学疗法诱导的转移，化学疗法诱导的肿瘤内在特性的变化和 肿瘤微环境驱动入侵导致复发。以前的研究表明 细胞迁移和细胞外基质（ECM）重塑与化学抗性TNBC有关。目标 该建议的是了解ECM对化学抗性和 化学疗法诱导的TNBC转移。 我们提供了初步数据，即在TNBC肿瘤中上调的个体蛋白具有抗性 化学疗法药物紫杉醇和组织蛋白酶B（CTSB）的表达，该蛋白酶降解了这些 ECM蛋白变成小片段，可以防止化学抗性的发展。我们将剖析 蛋白酶CTSB和ECM蛋白降解的机制会影响对紫杉醇的反应 TNBC以及这些片段是否可用于在体内跟踪和靶向化学抗性。我们也有 发现化学疗法治疗会导致乳腺肿瘤的ECM组成变化。 具体而言，紫杉醇治疗导致胶原蛋白的丰度增加，ECM蛋白是一种ECM蛋白 促进TNBC中的入侵和转移。我们的目标是确定分泌ECM蛋白的细胞类型 例如化学疗法治疗后胶原蛋白IV，确定这些ECM蛋白对 化学疗法诱导的转移，以及是否可以针对这些途径以防止发展 复发。 成功完成拟议的研究后，我们的贡献预计将是对 ECM蛋白在TNBC肿瘤中的上调如何有助于化学耐药性以及化学疗法如何改变 ECM促进复发和转移传播。这些贡献将是重要的，因为 所有TNBC患者接受化疗，转移性复发是当前未满足的临床需求。结果 从这些研究中将提供有关化学耐药机制和 化学疗法引起的转移，将使我们能够制定新的策略来跟踪，预测和克服 TNBC中的化学抗性。