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: 10199263
• 负责人: Glen S. Kwon
• 金额: $ 17.7万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199263
• 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; cytokine; drug development; effective therapy; immune checkpoint blockade; in vivo; infiltrating duct carcinoma; inhibitor/antagonist; interest; malignant breast neoplasm; nanodrug; novel; pre-clinical; prognostic; prognostic signature; recruit; standard of care; success; therapeutic candidate; therapeutic target; 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.

项目概要 在癌症的特征中，细胞外基质有助于调节每个特征 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，并与患者预后不良相关。生物物理和 来自纤维基质硬度的生化线索已成为转移步骤的关键调节因素。 级联反应，包括增加肿瘤细胞侵袭、炎症信号、循环肿瘤细胞和转移 生长出来的。此外，新兴研究表明，来自 ECM 的生物物理线索影响肿瘤内在 以及与免疫治疗耐药有关的外在因素。综上所述，这些数据表明基质 基质硬度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发挥着关键作用 由于人们对肿瘤 ECM 治疗的兴趣日益浓厚，目前尚未有直接有效的治疗方法 靶向乳腺癌基质。因此，我们建议开发一种有治疗作用的药物 直接破坏原发性和转移性细胞外基质的组装、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 FN 与 PEG 化-FUD 的组装随后将通过抑制胶原蛋白来减少肿瘤纤维化 沉积和纤维排列导致肿瘤生长和转移进展减少。我们 进一步假设纤连蛋白和胶原蛋白沉积的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增强治疗效果。我们 将在以下目标中检验我们的假设： 目标 1：确定 PEG 化 FUD 作为抗癌药物的功效 乳腺癌临床前模型的治疗。目标 2. 评估 PEGylated-FUD 对 免疫抑制信号传导增强抗 PD-L1 疗法以治疗转移性疾病。