ASPH Targeted Therapy for Chondrosarcoma
ASPH 软骨肉瘤靶向治疗
基本信息
- 批准号:10587671
- 负责人:
- 金额:$ 63.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-22 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAntibody-drug conjugatesAntineoplastic AgentsApoptosisApoptosis Regulation GeneAspartateBiologyBirthBone TissueCRISPR/Cas technologyCarcinomaCartilageCatalytic DomainCell LineCell ProliferationCell Surface ProteinsCell SurvivalCellsChemoresistanceChondrosarcomaClinical TrialsCytotoxic ChemotherapyDataDevelopmentDoxorubicinEffectivenessEmbryonic DevelopmentExcisionGene ExpressionGenesGoalsGrowthHumanIn VitroIntegral Membrane ProteinInvadedKnock-outLinkMalignant - descriptorMalignant Bone NeoplasmMalignant NeoplasmsMatrix MetalloproteinasesMetastatic ChondrosarcomaMetastatic Neoplasm to the LungMethodsMixed Function OxygenasesModelingMolecularMolecular TargetMusNational Cancer InstituteNeoplasm MetastasisNormal CellOperative Surgical ProceduresOutcomePathway interactionsPatientsPharmaceutical PreparationsPharmacotherapyPhenotypePrognosisProliferatingPublic HealthQuality of lifeReducing AgentsResearchResistanceRoleSignal TransductionSoft tissue sarcomaSupporting CellSurvival RateTestingVascular Endothelial Growth FactorsWorkcancer cellcancer drug resistancecancer therapychemotherapeutic agentchemotherapycomparative efficacycytotoxicdrug developmentdruggable targeteffective therapygain of functiongastrointestinal carcinomahuman monoclonal antibodiesimprovedin vivoin vivo Modelinhibitorinsightknock-downloss of functionmigrationmouse modelneoplastic cellnotch proteinnovelnovel therapeutic interventionnovel therapeuticsoncofetal antigenosteosarcomaprimary bone cancerprogramsreceptorsarcomasmall molecule inhibitorstandard of caresynergismtargeted cancer therapytargeted treatmenttherapeutic targettreatment strategytumortumor growthtumor progression
项目摘要
PROJECT SUMMARY/ABSTRACT
The long-term objective of this application is to improve the survival and quality of life for patients with
chondrosarcoma, a primary malignant bone tumor desperately in need of more effective treatments. The five-
year survival for chondrosarcoma, the most common bone sarcoma in adults, is an abysmal 10-25%, with most
patients succumbing to pulmonary metastases. Conventional cytotoxic chemotherapy has no effect on
chondrosarcoma, so the current standard of care is surgical resection. There has been no improvement in the
cure rate for chondrosarcoma in the last several decades. The goal of this proposal is to systematically evaluate
promising new treatment strategies that target aspartate β-hydroxylase (ASPH), a transmembrane protein that
is normally expressed during embryonic development, but not after birth. We have found that ASPH is re-
expressed in chondrosarcoma. In some carcinomas, ASPH signals through the Notch pathway to influence the
expression of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF), which support
cell proliferation, invasion, and metastasis. We have data suggesting that ASPH functions similarly in
chondrosarcoma. ASPH is highly expressed in >90% of chondrosarcomas, as are activated Notch and multiple
MMPs, and high ASPH expression correlates positively with tumor grade and poor long-term survival. Inhibition
of Notch is a long sought after but, as of yet, unachieved goal in cancer treatment. The work in this proposal will
advance ASPH as a potential therapeutic target by determining the relationship between ASPH and Notch in
chondrosarcoma. First, ASPH levels in human chondrosarcoma cell lines will be modulated using CRISPR-Cas9
gene editing, followed by treatment with a proven small molecule inhibitor (SMI) of ASPH. Changes in
proliferation, invasion, apoptosis, and Notch signaling will be used as mechanistic readouts of ASPH signaling
in vitro. Notch signaling will be manipulated in these ASPH-modulated cell lines with gain and loss of function
approaches to evaluate the role of Notch in ASPH signaling (Aim 1). Second, the role of ASPH and Notch in
chemotherapy resistance will be evaluated in human chondrosarcoma cell lines, and the ability of the SMI and
an ASPH-targeted antibody-drug conjugate (ADC) to enhance doxorubicin efficacy will be tested (Aim 2). Finally,
three different approaches to targeting ASPH will be evaluated in vivo using mouse chondrosarcoma models:
SMI inhibition of ASPH, SMI + doxorubicin, and an antibody-drug conjugate targeting ASPH linked to emtansine
(Aim 3). The completion of these aims will provide important insight into the biology of chondrosarcoma and
determine whether the therapeutic targeting of ASPH has potential as an effective strategy for the treatment of
these malignancies. The results may also have wider impact and be applicable to patients with other types of
bone and soft tissue sarcomas.
项目总结/摘要
该应用的长期目标是改善患有以下疾病的患者的生存率和生活质量:
软骨肉瘤是一种原发性恶性骨肿瘤,迫切需要更有效的治疗。五个-
软骨肉瘤是成人中最常见的骨肉瘤,其年存活率极低,仅为10- 25%,
死于肺转移的病人传统的细胞毒化疗对
软骨肉瘤所以目前的治疗标准是手术切除没有任何改善,
软骨肉瘤的治愈率。本提案的目标是系统地评估
有希望的新治疗策略,靶向天冬氨酸β-羟化酶(ASPH),一种跨膜蛋白,
通常在胚胎发育期间表达,但在出生后不表达。我们发现ASPH是一种
在软骨肉瘤中表达。在一些癌中,ASPH通过Notch途径信号传导以影响肿瘤细胞的增殖。
基质金属蛋白酶(MMPs)和血管内皮生长因子(VEGF)的表达,支持
细胞增殖、侵袭和转移。我们有数据表明,ASPH的功能类似于
软骨肉瘤ASPH在>90%的软骨肉瘤中高度表达,活化的Notch和多种
基质金属蛋白酶和高ASPH表达与肿瘤分级和不良长期生存率呈正相关。抑制
Notch是癌症治疗中长期追求但尚未实现的目标。本提案中的工作将
通过确定ASPH和Notch之间的关系,将ASPH作为潜在的治疗靶点,
软骨肉瘤首先,将使用CRISPR-Cas9调节人软骨肉瘤细胞系中的ASPH水平
基因编辑,然后用经证实的ASPH小分子抑制剂(SMI)治疗。变化
增殖、侵袭、凋亡和Notch信号传导将被用作ASPH信号传导的机制读数
体外Notch信号将在这些ASPH调节的细胞系中被操纵,具有功能的获得和丧失
评估Notch在ASPH信号传导中的作用的方法(Aim 1)。第二,ASPH和Notch在
将在人软骨肉瘤细胞系中评价化疗抗性,并且SMI和
将测试增强多柔比星功效的ASPH靶向抗体-药物缀合物(ADC)(目的2)。最后,
将使用小鼠软骨肉瘤模型在体内评价靶向ASPH的三种不同方法:
ASPH的SMI抑制、SMI +多柔比星和靶向与美坦辛连接的ASPH的抗体-药物缀合物
(Aim(3)第三章。这些目标的完成将为软骨肉瘤的生物学提供重要的见解,
确定ASPH的治疗靶向是否有潜力作为治疗以下疾病的有效策略:
这些恶性肿瘤该结果也可能具有更广泛的影响,并适用于其他类型的患者。
骨和软组织肉瘤。
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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RICHARD M TEREK其他文献
RICHARD M TEREK的其他文献
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{{ truncateString('RICHARD M TEREK', 18)}}的其他基金
Targeting CXCR4 and microRNA as Therapy for Chondrosarcoma
靶向 CXCR4 和 microRNA 治疗软骨肉瘤
- 批准号:
9105802 - 财政年份:2013
- 资助金额:
$ 63.86万 - 项目类别:
Targeting CXCR4 and microRNA as Therapy for Chondrosarcoma
靶向 CXCR4 和 microRNA 治疗软骨肉瘤
- 批准号:
8503036 - 财政年份:2013
- 资助金额:
$ 63.86万 - 项目类别:
Targeting CXCR4 and microRNA as Therapy for Chondrosarcoma
靶向 CXCR4 和 microRNA 治疗软骨肉瘤
- 批准号:
9315708 - 财政年份:2013
- 资助金额:
$ 63.86万 - 项目类别:
Targeting CXCR4 and microRNA as Therapy for Chondrosarcoma
靶向 CXCR4 和 microRNA 治疗软骨肉瘤
- 批准号:
8741948 - 财政年份:2013
- 资助金额:
$ 63.86万 - 项目类别:
RI COBRE: MECHANISMS OF ANGIOGENESIS IN CHONDROSARCOMA
RI COBRE:软骨肉瘤的血管生成机制
- 批准号:
8360477 - 财政年份:2011
- 资助金额:
$ 63.86万 - 项目类别:
RI COBRE: MECHANISMS OF ANGIOGENESIS IN CHONDROSARCOMA
RI COBRE:软骨肉瘤的血管生成机制
- 批准号:
8168037 - 财政年份:2010
- 资助金额:
$ 63.86万 - 项目类别:
RI COBRE: MECHANISMS OF ANGIOGENESIS IN CHONDROSARCOMA
RI COBRE:软骨肉瘤的血管生成机制
- 批准号:
7959905 - 财政年份:2009
- 资助金额:
$ 63.86万 - 项目类别:
RI COBRE: MECHANISMS OF ANGIOGENESIS IN CHONDROSARCOMA
RI COBRE:软骨肉瘤的血管生成机制
- 批准号:
7721008 - 财政年份:2008
- 资助金额:
$ 63.86万 - 项目类别:
RI COBRE: MECHANISMS OF ANGIOGENESIS IN CHONDROSARCOMA
RI COBRE:软骨肉瘤的血管生成机制
- 批准号:
7610823 - 财政年份:2007
- 资助金额:
$ 63.86万 - 项目类别:
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