Effect of CX4945 in tamoxifen resistant BCa
CX4945 在他莫昔芬耐药 BCa 中的作用
基本信息
- 批准号:10673636
- 负责人:
- 金额:$ 28.4万
- 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:2020-08-05 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:Antiestrogen TherapyAntineoplastic AgentsBreast CarcinomaClinicalDegradation PathwayDevelopmentDiagnosisDown-RegulationEndocrineEndocrine Gland NeoplasmsEstrogen AntagonistsEstrogen Receptor alphaEstrogen ReceptorsEstrogensGenomicsGoalsHormonesIncidenceLengthLigandsMediatingMetastatic Neoplasm to Lymph NodesModelingMolecular ChaperonesMutationOncogenicPatientsPhosphorylationPhosphotransferasesPlayPredispositionProtein IsoformsProteinsQuality of lifeReceptor SignalingRelapseReportingRepressionResistanceRoleSelective Estrogen Receptor ModulatorsSignal TransductionStimulation of Cell ProliferationTamoxifenTestingTissue MicroarrayTranscriptUbiquitinationVariantcasein kinase IIefficacious treatmentefficacy evaluationestrogen disruptionestrogenichormone therapyinhibitormalignant breast neoplasmnon-genomicpatient derived xenograft modelpharmacologicpreclinical studypreventreceptorrhotherapy resistanttumor xenografttumorigenesis
项目摘要
Non-genomic estrogen signaling has been implicated in mediating therapeutic resistance to anti-estrogen
therapies in breast carcinoma (BCa) and may contribute to the mitogenic effects of selective estrogen receptor
modulators (SERMS). ERα36 [a 36 Kd transcript variant of estrogen receptor alpha (ERα)] mediates non-
genomic estrogen signaling, and is implicated in anti-estrogen resistance and anti-estrogen induced
mitogenesis1. Dual inhibition of ERα66 (full length ERα) and ERα36 signaling might prove to be a more
efficacious mode of antihormonal therapy that avoids the acquisition of anti-estrogen induced resistance and
tumorigenesis. This can be achieved by pharmacological targeting of the common posttranslational regulatory
mechanisms (ie, phosphorylation) between the two isoforms. CX4945 (silmitasertib), a clinical stage CK2
inhibitor, represses protein levels of both ERα66 and ERα36. As such CX4945 might serve to uniquely disrupt
oncogenic kinase signaling as well as reduces stability of ERα isoforms in BCa. We hypothesize that CX4945
inhibits both genomic and nongenomic estrogenic signaling by functioning as an indirect pan-estrogen receptor
downregulator which disrupts both ERα66 and ERα36 expression in BCa.
In order to test this hypothesis we will:
Aim I. Investigate the role of the ERα66/36 /CK2 signaling axis in the development of tamoxifen resistance.
For this aim we hypothesize that CK2 promotes the development of 4HT resistance by promoting aberrant ERα
signaling. We will determine the incidence and causative role of altered ERα36 and CK2 expression in the
development of tamoxifen resistance in breast cancer.
Aim 2 Elucidate the mechanisms of CX4945 mediated downregulation of ERα66/36 in BCa. Here we
hypothesize that pharmacological inhibition of CK2 with CX4945 renders ERα isoforms susceptible to the 26S
proteasomal degradation pathway. We will ascertain the impact of CK2 mediated phosphorylation of ERα66/36 on
chaperone interaction, ubiquitination and subsequently the proteolytic degradation of ERα36.
Aim 3 Assess the antineoplastic efficacy of CX4945 in paired patient derived xenograft (PDX) models of
4HT sensitive and resistant models of BCa. We hypothesize that CX4945 will inhibit the progression of
tamoxifen-sensitive and tamoxifen-resistant (de novo and acquired) PDX tumors. PDX tumors from endocrine
sensitive patients will be used to generate models of acquired resistance, whereas de-novo resistance will be
modelled using PDX from patients with Y537S mutation.
The successful completion of these studies could lead to the use of CX4945 or similar CK2 inhibitors with indirect
pan-ERα downregulating functions in the treatment of hormone sensitive and hormone resistant breast cancer.
非基因组雌激素信号已涉及介导抗雌激素治疗抗性
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Breast Cancer Reconstruction: Design Criteria for a Humanized Microphysiological System.
- DOI:10.1089/ten.tea.2020.0372
- 发表时间:2021-02
- 期刊:
- 影响因子:0
- 作者:Trivia P Frazier;Christopher Williams;M. Henderson;T. Duplessis;Emma Rogers;Xiying Wu;K. Hamel;E. Martin;O. Mohiuddin;Shahensha Shaik;R. Devireddy;B. Rowan;Daniel Hayes;J. Gimble
- 通讯作者:Trivia P Frazier;Christopher Williams;M. Henderson;T. Duplessis;Emma Rogers;Xiying Wu;K. Hamel;E. Martin;O. Mohiuddin;Shahensha Shaik;R. Devireddy;B. Rowan;Daniel Hayes;J. Gimble
NURR1 Is Differentially Expressed in Breast Cancer According to Patient Racial Identity and Tumor Subtype.
- DOI:10.3390/biomedinformatics2040045
- 发表时间:2022-12
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
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Christopher Williams其他文献
Christopher Williams的其他文献
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{{ truncateString('Christopher Williams', 18)}}的其他基金
Using Digital Health Technology to Prevent Bullying and Cyberbullying among Elementary School Students
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- 批准号:
10822435 - 财政年份:2023
- 资助金额:
$ 28.4万 - 项目类别:
Effect of CX4945 in tamoxifen resistant BCa
CX4945 在他莫昔芬耐药 BCa 中的作用
- 批准号:
10228560 - 财政年份:2020
- 资助金额:
$ 28.4万 - 项目类别:
Effect of CX4945 in tamoxifen resistant BCa
CX4945 在他莫昔芬耐药 BCa 中的作用
- 批准号:
10458662 - 财政年份:2020
- 资助金额:
$ 28.4万 - 项目类别:
A High School Program for Preventing Prescription Drug Abuse
预防处方药滥用的高中计划
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9980826 - 财政年份:2017
- 资助金额:
$ 28.4万 - 项目类别:
A High School Program for Preventing Prescription Drug Abuse
预防处方药滥用的高中计划
- 批准号:
10226253 - 财政年份:2017
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$ 28.4万 - 项目类别:
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8855851 - 财政年份:2015
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Induction of a tumor-hostile breast cancer microenvironment by metformin
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- 批准号:
9058123 - 财政年份:2015
- 资助金额:
$ 28.4万 - 项目类别:
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8921161 - 财政年份:2014
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$ 28.4万 - 项目类别:
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