P2 - Targeting DII4-Notch Signaling in Ovarian Cancer
P2 - Targeting DII4-Notch Signaling in Ovarian Cancer
批准号:
7961936
负责人:
ANIL K SOOD
金额:
$19.94万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-09-01 至 2015-08-31
关键词:
AddressAffinityAngiogenesis InhibitorsAntibodiesApoptosisAscitesBiologicalBiopsyBlood VesselsCancer ModelCancer PatientCell Differentiation processClinicClinicalClinical ManagementClinical TrialsCoupledDataDevelopmentDiseaseDoseDown-RegulationDrug KineticsDrug resistanceEndothelial CellsEpigenetic ProcessFundingGeneticGoalsGrowthGrowth Factor InhibitionHumanHypoxiaImageIn VitroInstructionLigandsMalignant NeoplasmsMalignant neoplasm of ovaryMeasuresModalityModelingMolecularMonoclonal AntibodiesNeoplasm MetastasisNotch Signaling PathwayOvarianOvarian CarcinomaPathologic NeovascularizationPathway interactionsPatientsPerfusionPericytesPhasePhysiologicalPlayPrimary NeoplasmPrognostic FactorProgressive DiseasePublishingReceptor InhibitionRecurrenceRegimenRegulationResistanceRoleSignal TransductionTaxane CompoundTherapeuticTopotecanToxic effectTranslationsTumor BurdenVEGF TrapVascular Endothelial Growth Factor ReceptorVascular Endothelial Growth Factor Receptor-2Vascular Endothelial Growth FactorsVascular PermeabilitiesVascular blood supplyWomanWorkangiogenesisantiangiogenesis therapybevacizumabcancer cellchemotherapycombinatorialdensitydesignin vivoinhibitor/antagonistinsightnotch proteinnovelnovel strategiesnovel therapeutic interventionnovel therapeuticspre-clinicalreceptorresponsesuccesstaxanetreatment strategytumortumor growthtumor progression
中文摘要
项目SUK/IH/ARID(见说明):
原发卵巢癌的进行性生长和转移依赖于一种
充足的血液供应(血管生成)。血管内皮生长因子(VEGF)在血管生成中起重要作用
血管生成与卵巢癌的生长和发展。血管内皮细胞生长因子封锁显示出希望
在人类研究中。我们上一次资助期间的临床前和临床结果表明,一种新的
阻断血管内皮生长因子的途径(高亲和力的血管内皮生长因子诱骗受体、血管内皮生长因子陷阱或阿普利赛特)是高度有效的
与紫杉烷化疗联合有效。然而,尽管最初有反应,但大多数患者
最终发展成肿瘤,导致他们死亡,主要是由于药物的开发
抵抗。DII4(delta样配体4)/Notch信号通路最近被证明在一种
在血管生成中的重要作用,包括血管成熟、周细胞募集、分支和细胞
分化、增殖、存活和凋亡。我们的初步数据表明,当抑制DII4时
使用单抗(DII4-mAb或REGN421)与血管内皮生长因子抑制(AfLibercept)相结合,这是
联合用药显著减少了肿瘤负担和腹水,表明这种抗血管生成方案
有望成为一种新的治疗方式。然而,其药效机制尚不完全清楚。
明白了。我们推测,DII4/Notch信号通路在降低DII4/Notch信号通路的
抗血管内皮生长因子单药治疗和同时靶向血管内皮生长因子和DII4/Notch信号通路将增强疗效
抗血管生成治疗。这项提议的总体目标是制定新颖和有效的战略,以
靶向卵巢癌血管生成。在目前的提案中,我们将调查其功能意义
通过检测DII4在卵巢癌中的表达研究DII4/Notch信号通路在卵巢癌中的作用
细胞激活内皮细胞中的Notch信号,而阻断DII4/Notch信号是否与
在目标1中,REGN421解除了对体外血管生成的调控。在目标2中,我们将评估联合应用的疗效
利用AFLibercept和REGN421靶向VEGFA/EGFR/DII4/Notch信号通路的途径
活体原位卵巢癌模型。我们将使用抗DII4进行I/Lb期临床试验
单抗REGN421在AIM 3复发性卵巢癌患者中的应用
是相辅相成的,这项研究的发现应该允许设计新的治疗方法
卵巢癌患者的治疗方法
英文摘要
PROJECT SUK/IH/IARY (See instructions):
The progressive growth of primary ovarian cancer and metastasis is dependent on development of an
adequate blood supply (angiogenesis). Vascular endothelial growth factor (VEGF) plays a critical role in
angiogenesis and consequent ovarian cancer growrth and progression. VEGF blockade has shown promise
in human studies. Our pre-clinical and clinical results from the prior funding period demonstrate that a novel
approach (high-affinity VEGF decoy receptor, VEGF-Trap or aflibercept) for VEGF blockade was highly
effective in combination with taxane chemotherapy. However, despite initial responses, most patients
eventually develop tumor progression resulting in their demise, mainly due to the development of drug
resistance. The DII4 (delta-like ligand 4)/Notch signaling pathway has recently been shown to play an
important role in angiogenesis including vessel maturation, pericyte recruitment, branching and cell
differentiation, proliferation, survival and apoptosis. Our preliminary data indicate that when DII4 inhibition
using a monoclonal antibody (DII4-mAb or REGN421) was coupled with VEGF inhibition (aflibercept), this
combination strikingly reduced tumor burden and ascites, suggesting that this anti-angiogenesis regimen
holds promise as a novel therapeutic modality. However, the mechanisms of its potency are not fully
understood. We hypothesize that the DII4/Notch signaling pathway plays an important role in reducing the
efficacy of anti-VEGF monotherapy and targeting both VEGF and DII4/Notch signaling pathway will enhance
anti-angiogenic therapy. The overall goal of this proposal is to develop novel and effective strategies for
targeting ovarian cancer angiogenesis. In the current proposal, we will investigate the functional significance
of DII4/Notch signaling pathway in ovarian cancer by examining whether DII4 expression in ovarian cancer
cells activates Notch signaling in endothelial cells and whether blockade of DII4/Notch signaling with
REGN421 deregulates angiogenesis in vitro in Aim 1. In Aim 2, we will assess the efficacy of combinatorial
approaches for targeting VEGFA/EGFR/DII4/Notch signaling pathway with aflibercept and REGN421 using in
vivo orthotopic ovarian cancer models. We will conduct a Phase I/lb clinical trial using the anti-DII4
monoclonal antibody REGN421 in patients with recurrent ovarian carcinoma in Aim 3. Thus, all three Aims
are complementary to each other and findings of this study should allow the design of new therapeutic
approaches for women with ovarian cancer
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