Development of Potent Inhibitors of proto-oncogene PELP1 for Treating Advanced Breast Cancer
开发用于治疗晚期乳腺癌的原癌基因 PELP1 强效抑制剂
基本信息
- 批准号:10412909
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-10-01 至 2023-09-30
- 项目状态:已结题
- 来源:
- 关键词:ADME StudyAccountingAddressAggressive Clinical CourseAmericanAntiestrogen TherapyAromatase InhibitorsBiochemicalBiological MarkersBiological ModelsBreast Cancer ModelBreast Cancer PreventionBreast Cancer TreatmentBreast Cancer therapyCancer EtiologyCaringCessation of lifeClinicalClinical TreatmentCouplesDevelopmentDiagnosisDoseDrug KineticsEnvironmentEpigenetic ProcessEstrogen AntagonistsEstrogen receptor positiveExhibitsFemaleGeneral PopulationGlutamic AcidGoalsHealthcare SystemsIn VitroIncidenceKnowledgeLeadLeucineLiposomesMalignant NeoplasmsMass Spectrum AnalysisMaximum Tolerated DoseMediatingMilitary PersonnelModelingModificationMolecularMolecular Mechanisms of ActionNeoplasm MetastasisNuclear ReceptorsOncogenicOutcomePatientsPharmaceutical PreparationsPlayPopulationPre-Clinical ModelPrevalencePreventionProlineProteinsProto-OncogenesRepressionResearchResistanceResistance developmentRoleSignal TransductionSmall Interfering RNASouth TexasSpecificityTechnologyTestingTexasTherapeuticToxic effectVeteransWomanWorkXenograft procedureadvanced breast cancerbreast cancer progressionbreast cancer survivalcancer diagnosiscancer therapyclinically relevantclinically significantcost effectiveeffective therapyefficacy testinggenome sequencinghistone modificationin vitro Modelin vivoin vivo evaluationinhibitorinnovationknock-downmalignant breast neoplasmmilitary veteranmolecular subtypesmortalitynew therapeutic targetnovel therapeuticspatient derived xenograft modelpeptidomimeticspreventprognostic indicatorprogramsreceptor functionresponsesmall moleculesmall molecule inhibitortargeted cancer therapytargeted treatmenttherapeutic targettherapy developmenttherapy resistanttriple-negative invasive breast carcinomatumortumor progressiontumor xenograftwhole genome
项目摘要
Project summary
Breast cancer (BCa) is the second leading cause of cancer death in women. Among Servicewomen, BCa is the
most commonly diagnosed cancer, accounting for 30% of female cancers with increased prevalence in older
Veterans. BCa has distinct molecular subtypes; estrogen receptor (ER) positive and triple negative breast
cancer (TNBC). A significant portion of ER-positive BCa initially respond to anti-estrogens or aromatase inhibitors
but eventually exhibit unresponsiveness to therapy, develop therapy-resistant breast cancer (TR-BC), and
ultimately progress to incurable metastasis. Moreover, TNBC has a more aggressive clinical course and overall
lack of targeted therapies. Development of effective therapies for female Veterans with TR-BC or TNBC
represents the highest unmet need in breast cancer treatment. Our ongoing research on PELP1, an oncogenic
coregulator protein originally cloned in this lab, displays an integral role in multiple nuclear receptor (NR)
functions associated with BCa progression. PELP1 expression is commonly dysregulated in BCa eliciting a
conducive environment for epigenetic modifications. Concomitantly, PELP1 is a prognostic indicator for poorer
BCa survival and indicator of therapy resistance and metastases. We have developed a first-in-class small
molecule inhibitor of PELP1 (SMIP) displaying effectivity against TR-BC and TNBC. SMIPs block PELP1’s ability
to promote epigenetic modifications. The objective of this proposal is to further develop a lead SMIP into a novel
drug for the clinical treatment of TR-BC and TNBC. Our overarching hypothesis is that PELP1 couples NRs
with epigenetic modifiers; therefore, targeting the PELP1 axis with SMIPs will have a therapeutic utility in treating
both TR-BC and TNBC. In Aim 1, we will determine lead SMIPs mechanism of action using biochemical,
molecular, unbiased mass spectroscopy, and whole genome sequencing approaches. In Aim 2, we will optimize
SMIP derivatives and conduct studies establishing the maximum tolerated dose and dose efficacy in vivo using
TR-BC and TNBC models. In Aim 3, we will test the translatability of optimized SMIPs using therapy resistant
xenografts, metastatic models, and patient derived xenografts (PDX). This proposal is innovative as SMIPs block
signaling from multiple oncogenic PELP1 activated NRs to uniquely promote repression of epigenetic modifiers.
Successful completion of the proposed work will result in the development of a first-in-class cancer therapy
drug specifically addressing the current lack of TR-BC and TNBC targeted therapies. This research program is
significant as it is expected to aid in identifying therapeutic targets critical to the treatment and prevention of
advanced breast cancer in the population of Servicewomen.
项目总结
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 }}
Ratna K Vadlamudi其他文献
Ratna K Vadlamudi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('Ratna K Vadlamudi', 18)}}的其他基金
Development of Potent Inhibitors of proto-oncogene PELP1 for Treating Advanced Breast Cancer
开发用于治疗晚期乳腺癌的原癌基因 PELP1 强效抑制剂
- 批准号:
10044416 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Development of Potent Inhibitors of proto-oncogene PELP1 for Treating Advanced Breast Cancer
开发用于治疗晚期乳腺癌的原癌基因 PELP1 强效抑制剂
- 批准号:
10516093 - 财政年份:2019
- 资助金额:
-- - 项目类别:
相似海外基金
Unraveling the Dynamics of International Accounting: Exploring the Impact of IFRS Adoption on Firms' Financial Reporting and Business Strategies
揭示国际会计的动态:探索采用 IFRS 对公司财务报告和业务战略的影响
- 批准号:
24K16488 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Early-Career Scientists
Mighty Accounting - Accountancy Automation for 1-person limited companies.
Mighty Accounting - 1 人有限公司的会计自动化。
- 批准号:
10100360 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Collaborative R&D
Accounting for the Fall of Silver? Western exchange banking practice, 1870-1910
白银下跌的原因是什么?
- 批准号:
24K04974 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
A New Direction in Accounting Education for IT Human Resources
IT人力资源会计教育的新方向
- 批准号:
23K01686 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
An empirical and theoretical study of the double-accounting system in 19th-century American and British public utility companies
19世纪美国和英国公用事业公司双重会计制度的实证和理论研究
- 批准号:
23K01692 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
An Empirical Analysis of the Value Effect: An Accounting Viewpoint
价值效应的实证分析:会计观点
- 批准号:
23K01695 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Accounting model for improving performance on the health and productivity management
提高健康和生产力管理绩效的会计模型
- 批准号:
23K01713 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
CPS: Medium: Making Every Drop Count: Accounting for Spatiotemporal Variability of Water Needs for Proactive Scheduling of Variable Rate Irrigation Systems
CPS:中:让每一滴水都发挥作用:考虑用水需求的时空变化,主动调度可变速率灌溉系统
- 批准号:
2312319 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Standard Grant
New Role of Not-for-Profit Entities and Their Accounting Standards to Be Unified
非营利实体的新角色及其会计准则将统一
- 批准号:
23K01715 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improving Age- and Cause-Specific Under-Five Mortality Rates (ACSU5MR) by Systematically Accounting Measurement Errors to Inform Child Survival Decision Making in Low Income Countries
通过系统地核算测量误差来改善特定年龄和特定原因的五岁以下死亡率 (ACSU5MR),为低收入国家的儿童生存决策提供信息
- 批准号:
10585388 - 财政年份:2023
- 资助金额:
-- - 项目类别: