Engineering a multispecific receptor antagonist to inhibit cancer metastasis
设计多特异性受体拮抗剂来抑制癌症转移
基本信息
- 批准号:8749811
- 负责人:
- 金额:$ 20.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-01 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdhesionsAffinityAgglutininsAntibodiesAvidityBindingBinding ProteinsBiochemicalBiochemistryBiologicalBiological AssayBiological ProcessBreast Cancer CellCause of DeathCell ProliferationCell Surface ReceptorsCellsClinical ResearchCoupledDU145DevelopmentDiagnostic Neoplasm StagingDiseaseDisseminated Malignant NeoplasmEngineeringEpitopesExtracellular Matrix DegradationFDA approvedFlow CytometryGlioblastomaGoalsGrowthGrowth FactorHumanIndividualLengthLibrariesLigand BindingLigandsMDA MB 231Malignant NeoplasmsMalignant neoplasm of brainMalignant neoplasm of prostateMeasuresMediatingMethodsMolecular and Cellular BiologyMusNeoplasm MetastasisPartner in relationshipPatientsPeptidesPharmaceutical PreparationsPhosphorylationProcessProtein EngineeringProteinsRelative (related person)ResistanceSignal PathwaySignal TransductionSiteSpecificitySurfaceSurface of the ProstateTestingTherapeuticTherapeutic InterventionTreatment EfficacyUnited StatesUrokinaseUrokinase Plasminogen Activator ReceptorVariantVitronectinYeastsaggressive therapyangiogenesisbasecancer cellcancer typechemotherapycombinatorialdrug developmenteffective therapyflexibilityfluorophoreinhibitor/antagonistinnovationmalignant breast neoplasmmigrationmutantneoplastic cellneovasculaturenovelnovel strategiesoverexpressionpreventprostate cancer cellpublic health relevancereceptorreceptor bindingreceptor expressionresearch and developmentsmall moleculesomatomedin Bsuccesstherapeutic proteintherapeutic targettumortumor growthtumor progressiontumorigenesis
项目摘要
The urokinase-type plasminogen activator receptor (uPAR) has been found to be overexpressed on the
surface of cancer cells, as well as their associated neovasculature, in virtually every cancer type tested,
including primary, metastatic, and chemotherapy-resistant cancers. uPAR is an important master regulator that
drives extracellular matrix degradation and angiogenesis, and cancer cell proliferation, adhesion, and
migration. These processes in turn allow rapid tumor growth and metastasis to other sites in the body. Clinical
studies indicate overexpression of uPAR and its soluble ligand uPA are independent predictors of low diseasefree
and overall survival. Thus, uPAR is an extremely attractive target for therapeutic intervention; however, the
absence of an FDA-approved drug that inhibits uPAR highlights a critical need for new approaches to
effectively block the activity of this receptor. We will apply our expertise in molecular and cellular biology,
biochemistry, and protein engineering to develop a novel first-in-class biologic capable of effectively blocking
uPAR-mediated cancer growth, metastasis, and tumor-associated angiogenesis. Numerous uPAR antagonists
have been developed over the last two decades, including small molecules, peptides, protein ligands, and
antibodies. However, the efficacies of these inhibitors have been limited owing to their low affinity relative to
the native uPAR ligands, and/or their inability to effectively block uPAR functions that drive cancer growth and
metastasis. Protein engineering, combined with multispecific target binding, will generate in uPAR inhibitors
with orders of magnitude higher binding affinity compared to previously developed antagonists. The resulting
biologics have exciting potential to overcome critical barriers that have prevent development of successful
uPAR-targeted therapeutics, and would represent a potential breakthrough for targeted therapy of aggressive
cancers.
已经发现尿激酶型纤溶酶原激活物受体(uPAR)在血管内皮细胞上过表达。
癌细胞的表面,以及它们相关的新血管,在几乎每一种测试的癌症类型中,
包括原发性、转移性和化疗抗性癌症。uPAR是一种重要的主调节器,
驱动细胞外基质降解和血管生成,以及癌细胞增殖、粘附,
迁移这些过程反过来又允许肿瘤快速生长和转移到身体的其他部位。临床
研究表明,uPAR及其可溶性配体uPA的过度表达是低无病生存率的独立预测因子,
和总生存期。因此,uPAR是治疗干预的极其有吸引力的靶标;然而,
由于缺乏FDA批准的抑制uPAR的药物,因此迫切需要新的方法来
有效地阻断这种受体的活性。我们将运用我们在分子和细胞生物学方面的专业知识,
生物化学和蛋白质工程,以开发一种新型的一流的生物能够有效地阻止
uPAR介导的癌症生长、转移和肿瘤相关的血管生成。多种uPAR拮抗剂
在过去的二十年里,已经开发了包括小分子,肽,蛋白质配体,
抗体的然而,这些抑制剂的功效由于它们相对于药物的低亲和力而受到限制。
天然uPAR配体,和/或它们不能有效地阻断驱动癌症生长的uPAR功能,
转移蛋白质工程与多特异性靶点结合将产生uPAR抑制剂
与先前开发的拮抗剂相比具有高数量级的结合亲和力。所得
生物制剂具有令人兴奋的潜力,可以克服阻碍成功开发
uPAR靶向治疗,并将代表侵袭性肿瘤靶向治疗的潜在突破。
癌的
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
JENNIFER R COCHRAN其他文献
JENNIFER R COCHRAN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('JENNIFER R COCHRAN', 18)}}的其他基金
Engineered HGF-NK1 antagonists for Met-targeted cancer imaging and therapy
用于 Met 靶向癌症成像和治疗的工程化 HGF-NK1 拮抗剂
- 批准号:
8449727 - 财政年份:2010
- 资助金额:
$ 20.83万 - 项目类别:
Engineering high affinity tumor-targeting peptides against carbonic anhydrase IX
针对碳酸酐酶 IX 设计高亲和力肿瘤靶向肽
- 批准号:
7772227 - 财政年份:2010
- 资助金额:
$ 20.83万 - 项目类别:
Engineering high affinity tumor-targeting peptides against carbonic anhydrase IX
针对碳酸酐酶 IX 设计高亲和力肿瘤靶向肽
- 批准号:
8034243 - 财政年份:2010
- 资助金额:
$ 20.83万 - 项目类别:
Engineered HGF-NK1 antagonists for Met-targeted cancer imaging and therapy
用于 Met 靶向癌症成像和治疗的工程化 HGF-NK1 拮抗剂
- 批准号:
8657879 - 财政年份:2010
- 资助金额:
$ 20.83万 - 项目类别:
Engineered HGF-NK1 antagonists for Met-targeted cancer imaging and therapy
用于 Met 靶向癌症成像和治疗的工程化 HGF-NK1 拮抗剂
- 批准号:
8100279 - 财政年份:2010
- 资助金额:
$ 20.83万 - 项目类别:
Engineered HGF-NK1 antagonists for Met-targeted cancer imaging and therapy
用于 Met 靶向癌症成像和治疗的工程化 HGF-NK1 拮抗剂
- 批准号:
8257561 - 财政年份:2010
- 资助金额:
$ 20.83万 - 项目类别:
Engineering the Met receptor: a potent antagonist of tumor growth and metastasis
改造 Met 受体:肿瘤生长和转移的有效拮抗剂
- 批准号:
7539905 - 财政年份:2007
- 资助金额:
$ 20.83万 - 项目类别:
相似海外基金
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y004841/1 - 财政年份:2024
- 资助金额:
$ 20.83万 - 项目类别:
Research Grant
Defining a role for non-canonical mTORC1 activity at focal adhesions
定义非典型 mTORC1 活性在粘着斑中的作用
- 批准号:
BB/Y001427/1 - 财政年份:2024
- 资助金额:
$ 20.83万 - 项目类别:
Research Grant
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y005414/1 - 财政年份:2024
- 资助金额:
$ 20.83万 - 项目类别:
Research Grant
Development of a single-use, ready-to-use, sterile, dual chamber, dual syringe sprayable hydrogel to prevent postsurgical cardiac adhesions.
开发一次性、即用型、无菌、双室、双注射器可喷雾水凝胶,以防止术后心脏粘连。
- 批准号:
10669829 - 财政年份:2023
- 资助金额:
$ 20.83万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10587090 - 财政年份:2023
- 资助金额:
$ 20.83万 - 项目类别:
Improving Maternal Outcomes of Cesarean Delivery with the Prevention of Postoperative Adhesions
通过预防术后粘连改善剖宫产的产妇结局
- 批准号:
10821599 - 财政年份:2023
- 资助金额:
$ 20.83万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10841832 - 财政年份:2023
- 资助金额:
$ 20.83万 - 项目类别:
Prevention of Intraabdominal Adhesions via Release of Novel Anti-Inflammatory from Surface Eroding Polymer Solid Barrier
通过从表面侵蚀聚合物固体屏障中释放新型抗炎剂来预防腹内粘连
- 批准号:
10532480 - 财政年份:2022
- 资助金额:
$ 20.83万 - 项目类别:
I-Corps: A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions
I-Corps:一种可喷雾的组织结合水凝胶,可防止术后心脏粘连
- 批准号:
10741261 - 财政年份:2022
- 资助金额:
$ 20.83万 - 项目类别:
Sprayable Polymer Blends for Prevention of Site Specific Surgical Adhesions
用于预防特定部位手术粘连的可喷涂聚合物共混物
- 批准号:
10674894 - 财政年份:2022
- 资助金额:
$ 20.83万 - 项目类别: