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
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 }}
Satish K. Chitneni其他文献
Satish K. Chitneni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('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:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Research Grant














{{item.name}}会员




