Flourine-18 labeled MDM2 antagonists for PET imaging
用于 PET 成像的 Flourine-18 标记的 MDM2 拮抗剂
基本信息
- 批准号:9978523
- 负责人:
- 金额:$ 18.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-10 至 2022-01-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAddressAffinityAnimalsApoptosisBindingBiological AssayBiologyBreast AdenocarcinomaBreast Cancer ModelCancer cell lineCell LineCellsCharacteristicsChemical StructureClinicalClinical DataDNA RepairDataDevelopmentDistant MetastasisDouble MinutesDrug or chemical Tissue DistributionFeedbackFluorescent in Situ HybridizationFluorineGene AmplificationGenesGenetic TranscriptionGenetically Engineered MouseGenome StabilityGlioblastomaHumanImageImaging TechniquesImmunohistochemistryIn VitroInvestigationKineticsLabelLeadMCF7 cellMaintenanceMalignant NeoplasmsMeasuresMesylatesMethodsMolecularMonitorMusMutationNull LymphocytesOncogenicOncoproteinsPartition CoefficientPathway interactionsPatientsPeptidesPhase I Clinical TrialsPhenolsPlayPositron-Emission TomographyPropertyProtein OverexpressionProtein p53ProteinsRadiolabeledRoleSoft tissue sarcomaSpecificityStressSurface Plasmon ResonanceTP53 geneTechnologyTherapeuticTracerTumor Suppressor ProteinsTumor TissueX-Ray Computed Tomographyaffinity labelinganalogbasecancer cellclinical developmentdesigngenetic regulatory proteinimaging agentimaging approachimaging modalityimaging probeimaging studyin vivolipophilicitymalignant breast neoplasmmolecular imagingmouse modelneoplastic cellnew therapeutic targetnon-invasive imagingoutcome forecastoverexpressionpatient populationpre-clinicalpredictive markerpreventprotein expressionresponsesarcomascaffoldsenescencesmall moleculetargeted treatmenttooltreatment responsetumortumor progressionubiquitin-protein ligaseuptake
项目摘要
ABSTRACT
The tumor suppressor protein p53 plays a critical role in protecting cells against oncogenic transformation.
Consistent with this role, nearly 50% of all human cancers have a mutation in the p53 gene, rendering the p53
protein inactive. In tumors that are wild-type p53, the p53 function is often inhibited by the overexpression of
its negative regulatory protein, murine double minute 2 (MDM2). Studies suggests that MDM2 is
overexpressed in several human cancers, including breast cancer, sarcomas and glioblastoma, although at
different rates. MDM2 interacts with p53 in a negative feedback loop and targets the p53 protein for
proteasomal degradation, thereby inhibiting the tumor suppressive function of p53 in wild-type p53 tumors.
Hence, inhibition of MDM2 with small molecule antagonists or other molecular scaffolds such as stapled
peptides is being pursued as a therapeutic strategy for activating the p53 pathway in wild-type p53 cancers.
Whilst the preclinical and the early clinical data have demonstrated the promise of this therapeutic approach,
recent phase 1 clinical trials with small molecule MDM2 antagonists have indicated significant association
between pre-treatment MDM2 expression levels and therapeutic response in patients with acute myeloid
leukemia. These data suggest the need for selecting appropriate patients for MDM2 inhibition therapies and
the potential usefulness of MDM2 as a predictive biomarker for MDM2 targeted therapies. One of the critical
barriers for such studies is the lack of a noninvasive method for determining MDM2 overexpression status in
tumors. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), the most commonly used
methods for assessing MDM2 gene amplification and MDM2 protein overexpression in tumors, respectively,
are invasive and do not permit monitoring the treatment response in vivo. To address these needs, we
propose to develop radiolabeled probes for imaging the MDM2 protein expression levels in tumors
noninvasively with positron emission tomography (PET), a highly sensitive molecular imaging technique.
Building on the preliminary data we obtained in support of the project, we will synthesize fluorine-18 labeled
compounds that bind to the MDM2 protein with high affinity (Aim 1). The labeled compounds will be evaluated
for their potential to bind on MDM2 expressing tumors cells in vitro (Aim 2) and in mouse models of breast
cancer and soft tissue sarcomas in vivo (Aim 3) to identify a lead molecule for MDM2 imaging with PET. To
the best of our knowledge, this project would be the first study to develop PET imaging agents for the
oncoprotein MDM2. Successful development of a PET imaging approach for the MDM2 protein will provide a
valuable tool for studying MDM2-p53 biology in vivo and for investigation of novel therapies targeting MDM2 in
wild-type p53 cancers.
摘要
肿瘤抑制蛋白p53在保护细胞免受致癌转化中起关键作用。
与这种作用相一致的是,近50%的人类癌症在p53基因中存在突变,使得p53基因突变。
蛋白质失活。在野生型p53的肿瘤中,p53的功能通常被以下蛋白的过表达所抑制:
其负调节蛋白,鼠双微体2(MDM 2)。研究表明,MDM 2
在几种人类癌症中过表达,包括乳腺癌、肉瘤和胶质母细胞瘤,尽管在
不同的利率。MDM 2在负反馈环中与p53相互作用,并靶向p53蛋白,
蛋白酶体降解,从而抑制野生型p53肿瘤中p53的肿瘤抑制功能。
因此,用小分子拮抗剂或其他分子支架如钉合的MDM 2抑制是可能的。
肽作为激活野生型p53癌症中p53途径的治疗策略正在被研究。
虽然临床前和早期临床数据已经证明了这种治疗方法的前景,
最近关于小分子MDM 2拮抗剂的1期临床试验表明,
急性髓系白血病患者治疗前MDM 2表达水平与治疗反应之间的关系
白血病这些数据表明需要选择适当的患者进行MDM 2抑制治疗,
MDM 2作为MDM 2靶向治疗的预测生物标志物的潜在有用性。的一个关键
这些研究的障碍是缺乏一种非侵入性的方法来确定MDM 2过表达状态,
肿瘤的荧光原位杂交(FISH)和免疫组织化学(IHC),最常用的
分别评估肿瘤中MDM 2基因扩增和MDM 2蛋白过表达的方法,
是侵入性的并且不允许在体内监测治疗反应。为了满足这些需求,我们
建议开发放射性标记探针,用于成像肿瘤中MDM 2蛋白表达水平
正电子发射断层扫描(PET),一种高灵敏度的分子成像技术。
在我们获得的支持该项目的初步数据的基础上,我们将合成氟-18标记
以高亲和力结合MDM 2蛋白的化合物(Aim 1)。将对标记化合物进行评价
因为它们在体外(Aim 2)和乳腺癌小鼠模型中结合MDM 2表达肿瘤细胞的潜力,
癌症和软组织肉瘤(目标3),以确定一种用于PET成像MDM 2的先导分子。到
据我们所知,该项目将是第一个研究开发PET成像剂,
癌蛋白MDM 2。MDM 2蛋白PET成像方法的成功开发将提供
研究MDM 2-p53体内生物学和研究靶向MDM 2的新疗法的有价值的工具,
野生型p53癌症。
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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Satish K. Chitneni其他文献
Satish K. Chitneni的其他文献
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{{ truncateString('Satish K. Chitneni', 18)}}的其他基金
Imaging IDH1 Mutations in Glioma and Other Malignancies
胶质瘤和其他恶性肿瘤中 IDH1 突变的成像
- 批准号:
8788512 - 财政年份:2014
- 资助金额:
$ 18.82万 - 项目类别:
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