Targeting the Cancer Glycocalyx

靶向癌症糖萼

基本信息

批准号：
10593093
负责人：
Carolyn Bertozzi
金额：
$ 40.87万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593093
关键词：
Antibodies Binding Binding Proteins Cell Culture Techniques Cell Line Cell Nucleus Cell Survival Cell membrane Cell surface Cells Chemicals Complement Cultured Cells Disease Disease Progression Engineering Enzymes Epidermal Growth Factor Receptor Extracellular Matrix Extracellular Protein Eye Family Focal Adhesions Foundations Future Galectin 1 Glycobiology Glycocalyx Glycoconjugates Grant Growth Factor Receptors Human IGF Type 2 Receptor Immune Immune Evasion In Vitro Integrins Intervention Invaded Malignant Neoplasms Mediating Metals Methods Modality Modeling Mucin 1 protein Mucins Mus Neoplasm Metastasis Neuraminidase Nuclear Oncogenic Oncology Pathway interactions Patient-Focused Outcomes Pattern Peptide Hydrolases Phenotype Polymers Polysaccharides Proteins Receptor Cell Role Sialic Acids Signal Transduction Structure Testing Thick Vertebral column cancer biomarkers cancer cell candidate identification cell killing extracellular glycosylation invention malignant breast neoplasm mannose 6 phosphate mouse model mucinase next generation novel therapeutics overexpression physical property polymerization polypeptide programs protein degradation receptor sialic acid binding Ig-like lectin sugar targeted cancer therapy therapeutic candidate tool trafficking translational applications tumor tumor progression tumorigenesis uptake

项目摘要

PROJECT SUMMARY Cell surface glycans mediate interactions with receptors on other cells, in the extracellular matrix, or on the same cell membrane. Altered glycosylation has long been known as a hallmark of cancer. Two frequently observed cancer-associated phenotypes are hypersialylation and mucin overexpression. These cancer glycosignatures strongly correlate with disease aggressiveness and poor patient outcomes, but their functional contribution to cancer progression has been unclear. The broad objective of this program is to bring chemical tools to bear on this important problem in oncology, with an eye for developing new modes of intervention. An enabling tool for these studies are synthetic glycopolymers that we used to engineer discrete glycosylation patterns on live cells, or to engage specific glycan-binding proteins in a multivalent manner. In the previous granting period we made three major discoveries regarding the roles of cancer glycosignatures in disease: (1) Hypersialylation is a mechanism of immune evasion mediated through the Siglec family of sialic acid-binding immune cell receptors. Accordingly, immune cell killing of cancer cells can be potentiated by targeted cleavage of their cell-surface sialosides using antibody-sialidase conjugates. (2) Mucin overexpression enhances the thickness and stiffness of the glycocalyx, which promotes integrin clustering and focal adhesion signaling. This, in turn, enhances cell survival in vitro and promotes metastasis in mouse tumor models. And finally, (3) a glycan switching mechanism modulates partitioning of galectin-1, a prominent breast cancer marker, between a cell's glycocalyx and nucleus. Nuclear localization of galectin-1 drives breast cancer invasion, and this is inhibited by glycopolymers that sequester galectin-1 extracellularly. These discoveries form the foundation of the aims proposed in this renewal application. Aim 1 is a corollary to our discovery that cancer mucins drive oncogenesis. We will develop antibody-enzyme conjugates comprising mucin-specific proteases (aka “mucinases”) to deforest cancer cells. We will generate tool molecules using known bacterial mucinases, and also identify human mucinases for incorporation into therapeutic candidates. In Aim 2, we will construct next-generation glycopolymers with native polypeptide backbones. These will be employed for fundamental studies of cancer glycobiology and for translational applications in Aim 3. Finally, in Aim 3 we introduce a new strategy for targeting extracellular proteins for degradation using glycopolymers that hijack the mannose-6-phosphate receptor (M6PR) lysosomal trafficking pathway. We will construct antibody-M6P glycopolymer conjugates that bind oncogenic cell-surface molecules such as growth factor receptors and the cancer-associated mucin MUC1 and target them for lysosomal degradation via engagement of M6PR. This new therapeutic modality complements the popular PROTAC approach for targeting intracellular proteins for proteasomal degradation.

项目摘要细胞表面糖介导其他细胞上的受体，细胞外基质或在相同的细胞膜。长期以来，糖基化的改变一直被称为癌症的标志。经常两个观察到的与癌症相关的表型是高透明化和粘蛋白的过表达。这些癌症糖节性与疾病的侵略性和患者结局差密切相关，但其功能性对癌症进展的贡献尚不清楚。该计划的广泛目标是带来化学工具可以解决肿瘤学中这个重要问题，并着眼于开发新模式干预。这些研究的支持工具是我们用来设计的合成糖聚合物活细胞上的离散糖基化模式，或在多价中参与特定的聚糖结合蛋白方式。在上一个授予期内，我们就癌症的作用做出了三个主要发现疾病中的糖节原质：（1）超衰老是一种免疫进化的机制，是通过唾液酸结合免疫球受体的SIGLEC家族。根据，癌细胞的免疫球杀死可以通过使用抗体 - 硅烷酶偶联物的细胞表面唾液苷靶向切割，可以通过靶向裂解。（2）粘蛋白的过表达增强了糖蛋白的厚度和刚度，从而促进整联蛋白聚类和局灶性粘合信号传导。反过小鼠肿瘤模型。最后，（3）聚糖切换机理调制galectin-1，a 显着的乳腺癌标志物，在细胞的糖脂和核之间。半乳糖素1的核定位驱动乳腺癌的侵袭，这受到隔离元素1细胞外的糖聚合物的抑制。这些发现构成了此续签应用中提出的目标的基础。目标1是推论我们发现癌粘蛋白驱动肿瘤发生。我们将开发抗体 - 酶结合物包含粘蛋白特异性蛋白酶（又称粘蛋白酶”），以化力癌细胞。我们将生成工具使用已知细菌粘蛋白酶的分子，也鉴定出企业的人粘蛋白酶治疗候选人。在AIM 2中，我们将用天然多肽构建下一代糖聚合物骨干。这些将用于癌症生物学和翻译的基础研究 AIM 3中的应用。最后，在AIM 3中，我们引入了一种针对细胞外蛋白的新策略使用劫持甘露糖-6-磷酸受体（M6PR）溶酶体运输的糖聚合物降解路径。我们将构建结合致癌细胞表面分子的抗体-M6P糖聚合物偶联物例如生长因子受体和与癌症相关的粘蛋白MUC1，并将其靶向溶酶体通过M6PR参与而退化。这种新的治疗方式符合流行的Protac 靶向细胞内蛋白的方法用于蛋白酶体降解。