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

描述（由申请人提供）：Mucin 1 （MUC1）跨膜糖蛋白在大多数乳腺癌、前列腺癌、肺癌、结肠癌、胰腺癌和卵巢癌中异常过表达。据估计，在美国每年诊断出的140万例肿瘤中，超过90万例会异常表达MUC1。在正常上皮细胞中，MUC1在表皮边界表达，MUC1的正常生理功能是保护与外界环境接触的上皮细胞，如毒素、感染、自由基、酸和其他形式的应激。肿瘤通过过度表达MUC1来保护自己免受不良生长条件和抗癌药物治疗的影响。重要的是，MUC1的过表达也足以引起恶性转化。MUC1多肽表达为两个亚基，形成稳定的异二聚体。MUC1- n末端亚基（MUC1- n）通过与跨膜MUC1 c末端亚基（MUC1- c）结合而被拴在细胞表面。MUC1-N进入保护屏障，在细胞表面留下MUC1-C作为一个假定的受体，向细胞内部发出应激信号。对多种人类癌细胞系的研究表明，MUC1可以减轻抗癌药物诱导的细胞死亡。此外，MUC1siRNA敲低癌细胞中MUC1的表达与对基因毒性药物的敏感性增加有关。综上所述，这些发现表明MUC1阻断了细胞对化疗药物的凋亡反应。前沿药物开发专注于针对特定癌症的特定靶点。使用这一策略，许多药物取得了临床和经济上的成功。已批准的靶向细胞表面受体的药物包括针对ErbB2的赫赛汀。MUC1受体已成为开发新的抗癌药物最具吸引力的靶点之一。MUC1在细胞表面的表达为可溶性MUC1受体的发育提供了一个靶标，该受体可阻断MUC1的功能。Genus Oncology LLC参与开发靶向MUC1受体的GO-101和GO102（可溶性MUC1- Traps）， MUC1受体不脱落，负责肿瘤形成和化疗耐药。本建议书的具体目的是：1.拟定建议书。评估muc1陷阱（GO-101和GO-102）在muc1依赖性抑制癌细胞死亡和化疗耐药中的作用。2. 探讨GO-101或GO-102在表达MUC1的多种肿瘤异种移植模型中的体内疗效。公共卫生相关性：乳腺癌和肺癌是导致死亡的主要原因。MUC1蛋白在实验模型中促进了这些和其他类型癌症的发展，并在90%以上的人类肿瘤中高水平表达。我们提出的MUC1药物开发计划将为乳腺癌、肺癌和其他类型肿瘤的治疗提供潜在的新机会。

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.