Oncogenic Signaling by DF3/MUC1 in Human Breast Cancer

人类乳腺癌中 DF3/MUC1 的致癌信号传导

• 批准号: 8508862
• 负责人: DONALD W. KUFE
• 金额: $ 34.13万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508862
• 关键词: Address; Antineoplastic Agents; Apical; Binding Proteins; Bioavailable; Biological Assay; Breast Cancer Cell; Breast Cancer Treatment; C-Peptide; C-terminal; Cancer Patient; Cause of Death; Cell Nucleus; Cell membrane; Cell surface; Cells; Characteristics; Clinic; Cloning; Code; Cytoplasm; Cytoplasmic Tail; Development; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; ErbB Receptor Family Protein; Evaluation; Extracellular Domain; Family member; Funding; Glycoproteins; Grant; Growth; Human; Knockout Mice; Knowledge; Laboratories; Link; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mitochondria; Monitor; Mucin 1 protein; Mucins; Mus; N-terminal; Normal tissue morphology; Oncogene Proteins; Oncogenic; Patients; Peptides; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Positioning Attribute; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Research; Research Support; SRC gene; Signal Transduction; Stress; Tandem Repeat Sequences; Therapeutic; Therapeutic Agents; Toxic effect; Woman; Work; anticancer research; biological adaptation to stress; carcinogenesis; clinical practice; extracellular; improved; inhibitor/antagonist; insight; malignant breast neoplasm; member; novel strategies; novel therapeutics; overexpression; research clinical testing; small molecule; therapeutic target; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): Mucin 1 (MUC1) is aberrantly overexpressed in ~90% of human breast cancers and, as such, has been regarded as a highly attractive target for the development of new anti-cancer agents. However, progress in the identification of drugs that block MUC1 had been previously limited by a lack of understanding as to how MUC1 contributes to malignant progression. In this regard, MUC1 consists of two subunits, and early research focused on the shed extracellular mucin subunit (MUC1-N). Work supported by this grant has now demonstrated that the transmembrane MUC1-C subunit functions as an oncoprotein and is a druggable target for the development of novel therapeutic agents. MUC1-C represents a potentially selective target in that the Muc1 knock-out mouse is viable and has no evident phenotype. In addition, the MUC1-C subunit is normally positioned in an inactive state at the apical borders of mammary epithelial cells. With transformation and loss of polarity, MUC1-C associates with receptor tyrosine kinases at the breast cancer cell membrane and localizes to the cytoplasm, nucleus and mitochondria. The potential selectivity of MUC1-C as a target is further supported by the demonstration that MUC1-C inhibitors are highly effective in the treatment of human breast tumor xenografts in mice without normal tissue toxicity. The overall objective of the proposed work is to improve scientific knowledge, therapeutic capability and clinical practice by targeting MUC1-C with novel approaches that block its oncogenic function. Our hypothesis is that the MUC1-C oncoprotein is a druggable target that can be inhibited at the cell membrane and within the breast cancer cell. The proposed work will address this hypothesis by providing (i) new insights into how inhibition of MUC1-C function blocks growth and survival of breast cancer cells, and (ii) new therapeutic agents that will be evaluated preclinically for potential development in the clinic for the treatment of breast cancer. The Specific Aims are: (1) To assess potential therapeutic approaches that target the MUC1-C subunit extracellular domain at the breast cancer cell surface; (2) To evaluate the development of orally bioavailable MUC1-C peptide inhibitors that block its function in the cytoplasm; (3) To define the activity of peptide and small molecule inhibitors of MUC1-C function in the nucleus and mitochondria; and (4) To identify effective combinations of MUC1-C inhibitors with targeted anti-cancer agents for breast cancer treatment.

描述（由申请人提供）：粘蛋白1（MUC 1）在约90%的人乳腺癌中异常过表达，因此被认为是开发新抗癌药物的高度有吸引力的靶标。然而，由于对MUC 1如何促进恶性进展缺乏了解，以前在鉴定阻断MUC 1的药物方面的进展受到限制。在这方面，MUC 1由两个亚基组成，早期的研究集中在脱落的细胞外粘蛋白亚基（MUC 1-N）上。这项资助支持的工作现在已经证明跨膜MUC 1-C亚基作为癌蛋白发挥作用，并且是开发新型治疗药物的药物靶点。MUC 1-C代表了一种潜在的选择性靶点，因为Muc 1敲除小鼠是活的，没有明显的表型。此外，MUC 1-C亚基通常位于乳腺上皮细胞顶端边缘的非活性状态。MUC 1-C与乳腺癌细胞膜上的受体酪氨酸激酶结合，并定位于细胞质、细胞核和线粒体。MUC 1-C作为靶标的潜在选择性进一步得到以下证明的支持：MUC 1-C抑制剂在治疗小鼠中的人乳腺肿瘤异种移植物方面非常有效，而没有正常组织毒性。拟议工作的总体目标是通过用阻断其致癌功能的新方法靶向MUC 1-C来提高科学知识、治疗能力和临床实践。我们的假设是，MUC 1-C癌蛋白是一个药物靶点，可以在细胞膜和乳腺癌细胞内被抑制。拟议的工作将通过以下方式解决这一假设：（i）对MUC 1-C功能的抑制如何阻断乳腺癌细胞的生长和存活的新见解，以及（ii）将在临床前评估用于治疗乳腺癌的临床潜在发展的新治疗药物。具体目标是：（1）评估靶向乳腺癌细胞表面的MUC 1-C亚基胞外结构域的潜在治疗方法;（2）评估口服生物可利用的MUC 1-C肽抑制剂的开发，其阻断其在细胞质中的功能;（3）确定MUC 1-C功能的肽和小分子抑制剂在细胞核和线粒体中的活性;和（4）鉴定MUC 1-C抑制剂与靶向抗癌剂的有效组合用于乳腺癌治疗。