Oncogenic Signaling by DF3/MUC1 in Human Breast Cancer

描述(申请人提供)：粘蛋白1(MUC1)在约90%的人类乳腺癌中异常过表达，因此被认为是新抗癌药物开发的一个极具吸引力的靶点。然而，由于缺乏对MUC1如何促进恶性进展的了解，以前在识别阻断MUC1的药物方面的进展一直受到限制。在这一点上，MUC1由两个亚基组成，早期的研究集中在脱落的胞外粘蛋白亚基(MUC1-N)。由这笔赠款支持的工作现在已经证明，跨膜MUC1-C亚单位作为一种癌蛋白发挥功能，是开发新型治疗药物的可用药靶点。MUC1-C代表了一个潜在的选择性靶点，因为MUC1基因敲除的小鼠是活的，没有明显的表型。此外，MUC1-C亚基通常位于乳腺上皮细胞的顶端边缘，处于不活跃状态。随着极性的改变和丧失，MUC1-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。MUC1-C抑制剂在无正常组织毒性的小鼠体内治疗人乳腺肿瘤异种移植瘤中非常有效，这进一步支持了MUC1-C作为靶点的潜在选择性。这项拟议工作的总体目标是通过以阻断其致癌功能的新方法来靶向MUC1-C来提高科学知识、治疗能力和临床实践。我们的假设是，MUC1-C癌蛋白是一个可药物靶点，可以在细胞膜和乳腺癌细胞内被抑制。这项拟议的工作将通过提供(I)抑制MUC1-C功能如何阻止乳腺癌细胞的生长和存活的新见解来解决这一假设，以及(Ii)将在临床前评估用于乳腺癌治疗的潜在开发的新的治疗药物。其具体目的是：(1)评估针对乳腺癌细胞表面MUC1-C亚单位胞外结构域的潜在治疗方法；(2)评估口服生物可用MUC1-C多肽抑制剂的开发情况，以阻断其在细胞质中的功能；(3)确定MUC1-C功能的多肽和小分子抑制剂在细胞核和线粒体中的活性；以及(4)确定MUC1-C抑制剂与靶向抗癌药物的有效组合，用于乳腺癌的治疗。

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.