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 在癌症的特征中，细胞外基质对每个特征的调节起着重要作用 肿瘤进展的基本原理。重要的是，细胞外基质硬度和纤维组织 促进乳腺癌的整体进展，并与不良的患者预后相关。生物物理学和 来自纤维基质僵硬的生化信号已经成为转移过程中步骤的关键调节因素。 级联反应，包括肿瘤细胞侵袭增加、炎症信号、循环肿瘤细胞和转移 外延生长。此外，新出现的研究表明，来自ECM的生物物理信号影响肿瘤的内在 与免疫治疗抵抗有关的外在因素。综上所述，这些数据表明间质 基质僵硬可能是乳腺肿瘤免疫抑制的潜在机制之一。 微环境。尽管越来越多的证据表明生物物理线索在疾病进展中起着关键作用 随着靶向肿瘤细胞外基质治疗的兴趣与日俱增，目前还没有直接有效的治疗方法。 靶向乳腺癌的间质基质。因此，我们建议开发一种治疗有用的试剂来 直接破坏原发灶和转移灶内细胞外基质的组装、沉积和组织 乳腺癌临床治疗的肿瘤微环境。我们假设直接瞄准 聚乙二醇化FUD的FN组装随后将通过抑制胶原来减少肿瘤纤维化 沉积和纤维排列导致肿瘤生长和转移进展减少。我们 进一步假设，纤维连接蛋白和胶原沉积减少将限制促肿瘤的机械激活 炎症与免疫检查点阻断相结合，可提高治疗效果。我们 我将在以下目标验证我们的假设：目标1：确定聚乙二醇化FUD作为抗癌药物的疗效 乳腺癌临床前模型的治疗。目的2.评价聚乙二醇化氟尿嘧啶对糖尿病患者的影响 加强抗PD-L1治疗转移性疾病的免疫抑制信号。