Human MUC1 MUC1 Oncoprotein: Development of MUC1-decoy soluble receptors as anti-

人类 MUC1 MUC1 癌蛋白：开发 MUC1 诱饵可溶性受体作为抗

• 批准号: 7534921
• 负责人: Deepak Raina
• 金额: $ 10万
• 依托单位: GENUS ONCOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-09 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534921
• 关键词: Acids; Acute Myelocytic Leukemia; Amino Acids; Antibodies; Antineoplastic Agents; Apical; Apoptotic; Attenuated; Binding; Breast; Breast Carcinoma; C-terminal; Cancer cell line; Capital; Cause of Death; Cell Death; Cell Proliferation; Cell Surface Receptors; Cell surface; Cells; Cessation of life; Clinical; Colon; Condition; Development; Development, Other; Diagnosis; Economics; Environment; Epidermal Growth Factor Receptor; Epithelial Cells; Erbitux; Experimental Models; Free Radicals; Gefitinib; Genus Cola; Glycocalyx; Glycoproteins; Growth; Hematologic Neoplasms; Human; Infection; Left; Lung; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mucin 1 protein; Mucin-1 Staining Method; Mucins; Multiple Myeloma; N-terminal; Non-Hodgkin' s Lymphoma; Numbers; Oncogene Proteins; Ovary; Pancreas; Peptide Vaccines; Pharmaceutical Preparations; Physiological; Principal Investigator; Prostate; Protein Overexpression; Proteins; Public Health; Receptor Signaling; Research; Resistance; Roche brand of trastuzumab; Signal Transduction; Stress; Tandem Repeat Sequences; Toxin; Xenograft Model; cancer cell; cancer type; cell injury; chemotherapeutic agent; drug development; in vivo; oncology; polypeptide; programs; receptor; response; success; therapy resistant; tumor; tumor xenograft

DESCRIPTION (provided by applicant): The Mucin 1 (MUC1) transmembrane glycoprotein is aberrantly overexpressed by most carcinomas of the breast, prostate, lung, colon, pancreas and ovary. Estimates indicate that over 900,000 of the 1.4 million tumors diagnosed annually in the US will aberrantly express MUC1. In normal epithelial cells, MUC1 is expressed on the epical borders and the normal physiologic function of MUC1 is to protect epithelial cells that are in contact with the external environment such as toxins, infections, free radicals, acids and other forms of stress. Tumors have exploited this function by overexpressing MUC1 to protect themselves against adverse growth conditions and treatment with anti-cancer agents. Importantly, overexpression of MUC1 is also sufficient to cause malignant transformation. The MUC1 polypeptide is expressed as two subunits that forms a stable heterodimer. The MUC1-N-terminal subunit (MUC1-N) is tethered to the cell surface by binding to the transmembrane MUC1 C-terminal subunit (MUC1-C). MUC1-N is shed into the protective barrier, leaving MUC1-C at the cell surface as a putative receptor for signaling the presence of stress to the interior of the cell. Studies of diverse human cancer cell lines have demonstrated that MUC1 attenuates anti-cancer agents-induced cell death. Moreover, knockdown of MUC1 expression in carcinoma cells by MUC1siRNA was associated with increased sensitivity to genotoxic drugs. Taken together, these findings indicate that MUC1 blocks the apoptotic response to chemotherapeutic agents. Leading edge drug development is focused on specific targets for specific cancers. A number of drugs have achieved clinical and economic success using this strategy. Approved agents that target cell surface receptors include Herceptin which is directed against ErbB2. The MUC1 receptor has emerged as one of the most attractive targets for the development of new anti-cancer agents. Expression of MUC1 on the cell surface provides a target for the development of a soluble MUC1 receptor that blocks MUC1 function. Genus Oncology LLC is involved in developing agents GO-101 and GO102 (soluble MUC1- Traps) that target the MUC1 receptor that is not shed and is responsible for tumor formation and chemoresistance. The Specific Aims of the proposal are: 1. To assess the effects of MUC1-Traps (GO-101 and GO-102) on MUC1-dependent inhibition of cancer cell death and chemoresistance. 2. To determine the in vivo efficacy of GO-101 or GO-102 in multiple tumor xenograft models expressing MUC1. PUBLIC HEALTH RELEVANCE:Breast and Lung Cancer are the leading causes of death. The MUC1 protein contributes to the development of these and other types of cancers in experimental models and is expressed at high levels in over 90% of human tumors. Our proposed drug development program on MUC1 should provide potentially new opportunities for the treatment of breast, lung and other types of tumors.

描述（申请人提供）：大多数乳腺癌、前列腺癌、肺癌、结肠癌、胰腺癌和卵巢癌均异常过表达粘蛋白1（MUC 1）跨膜糖蛋白。据估计，在美国每年诊断的140万肿瘤中，有超过90万将异常表达MUC 1。在正常上皮细胞中，MUC 1在上皮边缘上表达，MUC 1的正常生理功能是保护与外部环境接触的上皮细胞，例如毒素、感染、自由基、酸和其他形式的应激。肿瘤已经通过过度表达MUC 1来利用这种功能来保护自己免受不利的生长条件和抗癌药物治疗的影响。重要的是，MUC 1的过表达也足以引起恶性转化。MUC 1多肽表达为形成稳定异源二聚体的两个亚基。MUC 1-N-末端亚基（MUC 1-N）通过与跨膜MUC 1 C-末端亚基（MUC 1-C）结合而栓系到细胞表面。MUC 1-N脱落进入保护屏障，在细胞表面留下MUC 1-C作为推定的受体，用于向细胞内部发出应激存在的信号。多种人类癌细胞系的研究已经证明MUC 1减弱抗癌剂诱导的细胞死亡。此外，MUC 1 siRNA敲低癌细胞中MUC 1表达与基因毒性药物敏感性增加相关。总之，这些发现表明MUC 1阻断了对化疗剂的凋亡反应。前沿药物开发专注于特定癌症的特定靶点。许多药物使用这种策略取得了临床和经济上的成功。批准的靶向细胞表面受体的药物包括针对ErbB 2的赫赛汀。MUC 1受体已成为开发新抗癌药物的最具吸引力的靶标之一。MUC 1在细胞表面上的表达为阻断MUC 1功能的可溶性MUC 1受体的形成提供了靶标。Genus Oncology LLC参与开发GO-101和GO 102（可溶性MUC 1- Traps），这些药物靶向不脱落的MUC 1受体，并负责肿瘤形成和化疗耐药性。该提案的具体目标是：1。评估MUC 1-Traps（GO-101和GO-102）对MUC 1依赖性抑制癌细胞死亡和化疗耐药性的影响。2.确定GO-101或GO-102在表达MUC 1的多种肿瘤异种移植物模型中的体内功效。公共卫生相关性：乳腺癌和肺癌是导致死亡的主要原因。MUC 1蛋白在实验模型中有助于这些和其他类型癌症的发展，并且在超过90%的人类肿瘤中以高水平表达。我们提出的MUC 1药物开发计划将为乳腺、肺和其他类型肿瘤的治疗提供潜在的新机会。