POTENTIATING BREAST CANCER THERAPIES BY TARGETING TUMOR-ASSOCIATED MACROPHAGE

通过靶向肿瘤相关巨噬细胞来增强乳腺癌治疗

• 批准号: 8788393
• 负责人: Suzie H. Pun
• 金额: $ 39.83万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788393
• 关键词: Ablation; Adjuvant; Adjuvant Therapy; Adverse effects; Alanine; Animals; Antigen-Presenting Cells; Apoptotic; Architecture; Bacteriophages; Binding; Biodistribution; Biological Assay; Biopsy; Blood; Bone Marrow; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer therapy; Cancer Etiology; Cells; Cessation of life; Clinical; Clinical Research; Cytotoxic T-Lymphocytes; Development; Dichloromethylene Diphosphonate; Disease Progression; Drug Delivery Systems; Endothelial Cells; Exhibits; Goals; Health; Hormones; Human; Immune; Immune response; Immune system; In Vitro; Inflammatory; Intravenous; Leukocytes; Ligands; Liposomes; Malignant Neoplasms; Mammary Neoplasms; Methods; Monitor; Mus; Myeloid Cells; Neoplasm Metastasis; Organ; Peptides; Peripheral Blood Mononuclear Cell; Phage Display; Population; Population Heterogeneity; Property; Rattus; Regulatory T-Lymphocyte; Resistance; Rest; Scanning; Severities; Site; Site-Directed Mutagenesis; Structure; T-Lymphocyte; Techniques; Technology; Testing; Toxic effect; Transgenic Mice; Translating; Translations; Woman; Work; adaptive immunity; angiogenesis; antiangiogenesis therapy; cancer cell; cancer diagnosis; cell growth; chemotherapy; cytotoxicity; density; immunoregulation; in vivo; intravenous administration; killings; macrophage; malignant breast neoplasm; mouse model; neoplastic cell; patient population; response; scaffold; standard care; targeted delivery; targeted sequencing; targeted treatment; trafficking; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): Current treatments for breast cancer focus on the killing malignant cells but there is a substantial population of patients for whom these approaches ultimately fail. The long-term objective of this work is to develop an adjuvant therapy that targets the tumor-promoting stroma of cancer as a way to potentiate current approaches. Tumor-associated macrophages (TAMs) are activated in the tumor microenvironment and facilitate disease progression by promoting angiogenesis and tumor cell growth, and by suppressing the adaptive immune response. We have recently identified a peptide that preferentially recognizes murine tumor-associated macrophage but not resting macrophage, other leukocytes, or tumor cells. In this work, we will prepare multivalent targeting constructs to deliver pro-apoptotic agents to TAMs in a mouse model of mammary cancer. In addition, we will develop analogous targeting peptides for human TAMs. These technologies will be combined in a new construct for targeted ablation of human TAMs. Our goal is to move this technology toward clinical development and to provide an adjuvant treatment that is effective even for women with hormone-unresponsive or triple negative breast cancer.

描述（由申请人提供）：目前乳腺癌的治疗集中在杀死恶性细胞，但有相当多的患者最终失败。这项工作的长期目标是开发一种靶向肿瘤促进基质的辅助治疗方法，以加强目前的方法。肿瘤相关巨噬细胞（TAM）在肿瘤微环境中被激活，并通过促进血管生成和肿瘤细胞生长以及通过抑制适应性免疫应答来促进疾病进展。我们最近发现了一种肽，优先识别小鼠肿瘤相关的巨噬细胞，但不休息的巨噬细胞，其他白细胞，或肿瘤细胞。在这项工作中，我们将制备多价靶向结构，以提供促凋亡剂的TAM在小鼠乳腺癌模型。此外，我们还将开发用于人TAM的类似靶向肽。这些技术将结合在一个新的结构中，用于人体TAM的靶向消融。我们的目标是将这项技术推向临床开发，并提供一种即使对乳腺癌无反应或三阴性乳腺癌女性也有效的辅助治疗。