Use of antifibronectin agents to target fibrosis in mammary cancer

使用抗纤连蛋白药物治疗乳腺癌纤维化

• 批准号: 8692716
• 负责人: Patricia J Keely
• 金额: $ 19.05万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692716
• 关键词: Affect; Animal Model; Binding; Binding Proteins; Biological Assay; Breast Carcinoma; Carcinoma; Cardiovascular Models; Cell surface; Cells; Chemicals; Collagen; Collagen Fibril; Deposition; Development; Drug Targeting; Engineering; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Fibronectins; Fibrosis; Gel; Generations; Glycoproteins; Image; Imaging technology; Imatinib mesylate; Immune; Implant; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Institutes; Integrins; Lead; Leukocytes; MDA MB 231; Malignant Epithelial Cell; Mammary Neoplasms; Mammary gland; Modeling; Monitor; Mus; Neoplasm Metastasis; Nude Mice; Peptides; Pharmacologic Substance; Proteoglycan; Serum; Site; Streptococcus pyogenes; Structure; System; Techniques; Testing; Therapeutic; Time; Tissues; Tumorigenicity; Vascularization; Work; abstracting; base; breast density; cell motility; cytokine; density; fibrillogenesis; high throughput screening; inhibitor/antagonist; injured; intravital imaging; malignant breast neoplasm; meetings; novel; public health relevance; screening; second harmonic; small molecule; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Abstract Dense mammary tissues are 4-5 times more likely to generate tumors than non-dense tissues, such that up to a third of all breast cancers originate in mammographically dense tissue. Increased breast density arises from a significant increase in deposition of extracellular matrix (ECM) constituents, in particular, collagen and fibronectin (FN). Recent studies in murine models have shown that increased collagen density promotes mammary tumor formation and progression. FN is a serum and extracellular matrix glycoprotein whose deposition into fibrillar structures precedes and controls collagen fibril formation in a variety of systems studied. Deposition of fibronectin and contributes to inflammation and fibrosis by recruitment of immune and inflammatory cells that produce pro-fibrotic cytokines. Fibronectin is also a critical component of neo- vascularization, an important component in tumor growth. In contrast to collagen, which can self-assemble, FN fibrillogenesis is tightly controlled by molecules at cell surfaces. We postulate that FN assembly is potentially a drug target and may create an opportunity to regulate subsequent collagen deposition. We hypothesize that inhibitors of FN matrix assembly will diminish fibrosis observed during breast carcinoma progression, and will decrease tumor progression. Our objective is to identify small molecule inhibitors of FN assembly that may be utilized as therapeutics to decrease breast carcinoma incidence, tumorigenicity, and/or metastasis. Two types of inhibitors will be tested. The first type of inhibitor is a peptide derived from Streptococcus pyogenes, termed FUD for Functional Upstream Domain, which we have characterized extensively as a potent and specific inhibitor of FN assembly. Others have utilized FUD in a murine model of cardiovascular remodeling where it inhibited FN and collagen assembly, leukocyte infiltration and inflammation at the injured site. The second type of inhibitors are small molecules identified through a pilot high throughput screen using a FN assembly assay we developed. We chose three of the resulting inhibitors to test in collagen-dense murine models of mammary carcinoma and propose to characterize and test novel inhibitors resulting from a larger screen to take place at the Broad Institute (Cambridge, MA). Two Specific Aims are proposed: 1) Determine if FN deposition affects tumorigenicity of collagen-dense breast carcinomas in mice; 2) Identify and characterize new small molecules that disrupt FN fibrillogenesis derived from High Throughput Screening at the Broad Institute for their efficacy in blocking fibrosis and tumor progression in mouse mammary carcinoma models. The proposed work is novel and significant in that, even though it is well established that collagen alignment and fibrosis accompany tumor progression, the control of collagen and extracellular matrix deposition has not been identified as "druggable" in the treatment of tumors. Our group combines the needed expertise in collagen dense mammary carcinoma animal models, access to small molecule screening, and state-of-the art intravital imaging technology to identify relevant probes to be potentially developed into therapeutics against breast cancer.

描述(申请人提供)：致密的乳腺组织发生肿瘤的可能性是非致密组织的4-5倍，因此多达三分之一的乳腺癌起源于乳房X光检查致密的组织。乳房密度的增加源于细胞外基质(ECM)成分的显著增加，特别是胶原和纤维连接蛋白(FN)。最近在小鼠模型上的研究表明，胶原密度增加促进了乳腺肿瘤的形成和发展。FN是一种血清和细胞外基质糖蛋白，在许多研究系统中，它在纤维结构中的沉积先于并控制胶原原纤维的形成。纤维连接蛋白的沉积，并通过重新招募产生促纤维化细胞因子的免疫细胞和炎性细胞来促进炎症和纤维化。纤维连接蛋白也是新生血管的关键成分，是肿瘤生长的重要成分。与可以自我组装的胶原蛋白不同，纤维连接蛋白的形成受到细胞表面分子的严格控制。我们假设FN程序集可能是一个 药物靶点，并可能创造一个机会，以调节随后的胶原沉积。我们假设FN基质组装的抑制剂将减少乳腺癌进展过程中观察到的纤维化，并将减缓肿瘤进展。我们的目标是寻找FN装配的小分子抑制物，以降低乳腺癌的发病率、致瘤性和/或转移。将测试两种类型的抑制剂。第一种类型的抑制物是一种来源于化脓性链球菌的多肽，称为FUD，即功能上游结构域，我们广泛地表征了它是一种有效和特异的FN组装抑制物。其他人则将FUD用于心血管重塑的小鼠模型，在该模型中，FUD抑制了FN和胶原蛋白的组装，抑制了损伤部位的白细胞渗透和炎症。第二种类型的抑制剂是通过使用我们开发的FN组装试验进行的中试高通量筛选而确定的小分子。我们选择了三种由此产生的抑制剂在胶原蛋白致密的乳腺癌小鼠模型中进行测试，并提议在布罗德研究所(马萨诸塞州剑桥)进行更大规模的筛查来表征和测试新的抑制剂。提出了两个特定的目标：1)确定FN沉积是否影响小鼠致胶原密度高的乳腺癌的致瘤性；2)鉴定和表征新的能够干扰FN纤维形成的小分子，这些小分子来自布罗德研究所的高通量筛选，目的是为了研究它们在阻断小鼠乳腺癌模型中的纤维化和肿瘤进展方面的有效性。这项拟议的工作具有新颖性和重要意义，因为尽管已经确定胶原排列和纤维化伴随着肿瘤的进展，但对胶原和细胞外基质沉积的控制在肿瘤治疗中并未被确定为“可用药”。我们的团队结合了致密胶原蛋白乳腺癌动物模型、小分子筛查和最先进的活体成像技术方面所需的专业知识，以确定可能被开发为乳腺癌治疗药物的相关探针。