Direct therapeutic intervention of the tumor microenvironment with a potent inhibitor of fibronectin assembly

使用纤连蛋白组装的有效抑制剂对肿瘤微环境进行直接治疗干预

• 批准号: 10409814
• 负责人: Glen S. Kwon
• 金额: $ 20.92万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409814
• 关键词: Architecture; Automobile Driving; Binding Proteins; Biochemical; Biological Availability; Biology; Biophysics; Breast; Breast Cancer Detection; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; Cells; Clinical Data; Clinical Treatment; Clinical Trials; Collagen; Collagen Fiber; Collagen Fibril; Cues; Data; Deposition; Disease; Disease Progression; Enzymes; Extracellular Matrix; Fiber; Fibronectins; Fibrosis; Future; Goals; Heart Diseases; Immune; Immune Evasion; Immune response; Immunosuppression; Immunotherapy; Infiltration; Inflammation; Inflammatory; Innovative Therapy; Kidney Diseases; Light; Link; Malignant Neoplasms; Mammary Neoplasms; Mechanics; Neoadjuvant Therapy; Neoplasm Circulating Cells; Neoplasm Metastasis; Pathologic; Patient-Focused Outcomes; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Play; Pre-Clinical Model; Primary Neoplasm; Proteomics; Regulation; Renal Tissue; Research; Resistance; Safety; Signal Pathway; Signal Transduction; Specificity; Streptococcus pyogenes; Structure; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Treatment Efficacy; Tumor Cell Invasion; Tumor stage; Tumor-associated macrophages; Vascular Diseases; Work; advanced breast cancer; alternative treatment; anti-PD-L1 therapy; base; breast cancer progression; cancer therapy; chemotherapy; cyclooxygenase 2; drug development; effective therapy; immune checkpoint blockade; in vivo; infiltrating duct carcinoma; inhibitor; interest; malignant breast neoplasm; nanodrug; novel; pre-clinical; profibrotic cytokine; prognostic; prognostic signature; recruit; standard of care; success; therapeutic candidate; therapeutic target; translational potential; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT SUMMARY Among the hallmarks of cancer, the extracellular matrix contributes to the regulation of each of the hallmark principles underlying tumor progression. Importantly, extracellular matrix stiffness and fiber organization enhance overall breast cancer progression and are associated with poor patient outcome. Biophysical and biochemical cues from fibrillar matrix stiffness have emerged as key regulators of steps in the metastatic cascade, including increased tumor cell invasion, inflammatory signaling, circulating tumor cells, and metastatic outgrowth. Moreover, emerging studies demonstrate that biophysical cues from the ECM impact tumor intrinsic and extrinsic factors implicated in immunotherapy resistance. Taken together, this data suggests that stromal matrix stiffness may be one of the underlying mechanisms driving immunosuppression in the breast tumor microenvironment. Despite the growing evidence that biophysical cues play a key role in disease progression and the mounting interest in therapeutically targeting tumor ECM, there has yet to be an effective therapy directly targeting the stromal matrix in breast cancer. Therefore, we propose to develop a therapeutically useful agent to directly disrupt extracellular matrix assembly, deposition, and organization within the primary and metastatic tumor microenvironments for the clinical treatment of breast cancer. We hypothesize that directly targeting FN assembly with PEGylated-FUD will subsequently reduce tumor fibrosis by inhibiting collagen deposition and fiber alignment resulting in decreased tumor growth and metastatic progression. We further hypothesize that reduced fibronectin and collagen deposition will limit mechanical activation of pro-tumor inflammation resulting in enhanced therapeutic efficacy in combination with immune checkpoint blockade. We will test our hypothesis in the following aims: Aim 1: Determine the efficacy of PEGylated FUD as an anti-cancer therapy in pre-clinical models of breast cancer. Aim 2. Evaluate the impact of PEGylated-FUD on immunosuppressive signaling to enhance anti-PD-L1 therapy for treatment of metastatic disease.

项目总结