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: 8585985
• 负责人: Patricia J Keely
• 金额: $ 16.37万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8585985
• 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; 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.

致密乳腺组织产生肿瘤的可能性是非致密乳腺组织的4-5倍，因此多达三分之一的乳腺癌起源于乳房x光检查的致密组织。乳腺密度增加是由于细胞外基质（ECM）成分沉积的显著增加，特别是胶原蛋白和纤维连接蛋白（FN）。最近对小鼠模型的研究表明，胶原蛋白密度的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，在多种研究系统中，其沉积到纤维结构中先于并控制胶原纤维的形成。纤维连接蛋白的沉积，并通过募集产生促纤维化细胞因子的免疫和炎症细胞来促进炎症和纤维化。纤维连接蛋白也是新血管形成的重要组成部分，是肿瘤生长的重要组成部分。胶原蛋白可以自我组装，与之相反，FN纤维形成受到细胞表面分子的严格控制。我们假设FN装配是潜在的