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.

项目摘要 在癌症的标志中，细胞外基质有助于对每个标志的调节 肿瘤进展的原理。重要的是，细胞外基质刚度和纤维组织 增强整体乳腺癌的进展，并与患者不良结局有关。生物物理和 来自原纤维基质刚度的生化提示已成为转移性步骤的关键调节因子 级联，包括增加肿瘤细胞侵袭，炎症信号，循环肿瘤细胞和转移性 出生。此外，新兴研究表明，来自ECM的生物物理提示会影响肿瘤的固有 以及与免疫疗法抗性有关的外部因素。综上所述，这些数据表明基质 基质刚度可能是驱动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提示在疾病进展中起关键作用 并且对靶向肿瘤ECM的兴趣不断增加，尚未直接进行有效的疗法 靶向乳腺癌中基质基质。因此，我们建议开发一种具有治疗有用的药物 直接破坏主要和转移性内的细胞外基质组件，沉积和组织 用于乳腺癌临床治疗的肿瘤微环境。我们假设这是直接针对的 带有卵毛的FN组装将随后通过抑制胶原蛋白来减少肿瘤纤维化 沉积和纤维比对导致肿瘤生长和转移性进展减少。我们 进一步假设减少的纤连蛋白和胶原蛋白沉积将限制促肿瘤的机械激活 炎症导致与免疫检查点阻断结合使用的治疗功效增强。我们 将在以下目的中检验我们的假设：目标1：确定pegypated FUD作为反癌的功效 乳腺癌临床前模型的治疗。 AIM 2。评估PEGGERATED FUD对 免疫抑制信号传导可增强抗PD-L1治疗用于治疗转移性疾病。