Targeting the Cancer Glycocalyx
靶向癌症糖萼
基本信息
- 批准号:10593093
- 负责人:
- 金额:$ 40.87万
- 依托单位:
- 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:
- 关键词:AntibodiesBindingBinding ProteinsCell Culture TechniquesCell LineCell NucleusCell SurvivalCell membraneCell surfaceCellsChemicalsComplementCultured CellsDiseaseDisease ProgressionEngineeringEnzymesEpidermal Growth Factor ReceptorExtracellular MatrixExtracellular ProteinEyeFamilyFocal AdhesionsFoundationsFutureGalectin 1GlycobiologyGlycocalyxGlycoconjugatesGrantGrowth Factor ReceptorsHumanIGF Type 2 ReceptorImmuneImmune EvasionIn VitroIntegrinsInterventionInvadedMalignant NeoplasmsMediatingMetalsMethodsModalityModelingMucin 1 proteinMucinsMusNeoplasm MetastasisNeuraminidaseNuclearOncogenicOncologyPathway interactionsPatient-Focused OutcomesPatternPeptide HydrolasesPhenotypePolymersPolysaccharidesProteinsReceptor CellRoleSialic AcidsSignal TransductionStructureTestingThickVertebral columncancer biomarkerscancer cellcandidate identificationcell killingextracellularglycosylationinventionmalignant breast neoplasmmannose 6 phosphatemouse modelmucinasenext generationnovel therapeuticsoverexpressionphysical propertypolymerizationpolypeptideprogramsprotein degradationreceptorsialic acid binding Ig-like lectinsugartargeted cancer therapytherapeutic candidatetooltraffickingtranslational applicationstumortumor progressiontumorigenesisuptake
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
细胞表面聚糖介导与其他细胞上、细胞外基质中或细胞外基质上的受体的相互作用。
相同的细胞膜。糖基化改变长期以来被认为是癌症的标志。2经常
观察到的癌症相关表型是唾液酸化过度和粘蛋白过表达。这些癌
糖信号与疾病的侵袭性和不良的患者结果密切相关,但其功能性
对癌症进展的贡献尚不清楚。该计划的主要目标是
化学工具来解决肿瘤学中的这一重要问题,并着眼于开发新的模式
干预。这些研究的一个有利工具是我们用来设计的合成糖共聚物,
活细胞上的离散糖基化模式,或以多价糖基化模式结合特异性聚糖结合蛋白。
方式
在上一个资助期,我们有三个关于癌症作用的重大发现,
(1)高唾液酸化是一种免疫逃避的机制,通过糖基化介导。
唾液酸结合免疫细胞受体的Siglec家族。因此,癌细胞的免疫细胞杀伤可以
通过使用抗体-唾液酸酶缀合物靶向切割它们的细胞表面唾液酸苷来增强。(二)
粘蛋白过度表达增加了糖萼的厚度和硬度,从而促进整合素
聚集和粘着斑信号传导。这反过来又增强了细胞在体外的存活,并促进了肿瘤的转移。
小鼠肿瘤模型。最后,(3)聚糖转换机制调节半乳糖凝集素-1的分配,
一个突出的乳腺癌标志物,位于细胞的糖萼和细胞核之间。Galectin-1的核定位
驱动乳腺癌侵袭,而这可以通过在细胞外隔离半乳凝素-1的糖聚合物来抑制。
这些发现构成了本次更新申请中提出的目标的基础。目标1是一个
这是我们发现癌症粘蛋白驱动肿瘤发生的必然结果。我们将开发抗体-酶结合物
包括粘蛋白特异性蛋白酶(也称为“粘蛋白酶”)以消灭癌细胞。我们将生成工具
本发明还使用已知的细菌粘蛋白酶来鉴定人粘蛋白酶以用于掺入到
治疗候选人。目标二是利用天然多肽构建新一代糖基共聚物
骨干这些将用于癌症糖生物学的基础研究和翻译
在Aim 3中的应用最后,在目标3中,我们介绍了一种靶向细胞外蛋白的新策略,
使用劫持甘露糖-6-磷酸受体(M6 PR)的糖聚合物的降解
通路我们将构建结合致癌细胞表面分子的抗体-M6 P糖聚合物缀合物
如生长因子受体和癌症相关粘蛋白MUC 1,并将它们靶向溶酶体
通过M6 PR的接合进行降解。这种新的治疗方式补充了流行的PROTAC
用于靶向细胞内蛋白质以进行蛋白酶体降解的方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Carolyn Bertozzi其他文献
Carolyn Bertozzi的其他文献
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{{ truncateString('Carolyn Bertozzi', 18)}}的其他基金
Stanford ChEM-H Chemistry/Biology Interface Predoctoral Training Program
斯坦福大学 ChEM-H 化学/生物界面博士前培训计划
- 批准号:
10427435 - 财政年份:2021
- 资助金额:
$ 40.87万 - 项目类别:
Stanford ChEM-H Chemistry/Biology Interface Predoctoral Training Program
斯坦福大学 ChEM-H 化学/生物界面博士前培训计划
- 批准号:
10620316 - 财政年份:2021
- 资助金额:
$ 40.87万 - 项目类别:
Stanford ChEM-H Chemistry/Biology Interface Predoctoral Training Program
斯坦福大学 ChEM-H 化学/生物界面博士前培训计划
- 批准号:
10269291 - 财政年份:2021
- 资助金额:
$ 40.87万 - 项目类别:
Making glycoproteomics via mass spectrometry more accessible to the greater scientific community
让广大科学界更容易利用质谱法进行糖蛋白组学
- 批准号:
9893341 - 财政年份:2016
- 资助金额:
$ 40.87万 - 项目类别:
Stanford Chem-H Chemistry/Biology Interface Predoctoral Training Program
斯坦福 Chem-H 化学/生物界面博士前培训计划
- 批准号:
9302802 - 财政年份:2016
- 资助金额:
$ 40.87万 - 项目类别:
Making glycoproteomics via mass spectrometry more accessible to the greater scientific community
让更广泛的科学界更容易利用质谱法进行糖蛋白组学
- 批准号:
9334156 - 财政年份:2016
- 资助金额:
$ 40.87万 - 项目类别:
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