Targeting centrosome‐mitotic kinases as a novel therapeutic approach against breast cancers in Hispanic/Latinas.
靶向中心体有丝分裂激酶作为治疗西班牙裔/拉丁裔乳腺癌的新方法。
基本信息
- 批准号:10539820
- 负责人:
- 金额:$ 48.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAfricanAfrican CaribbeanAfrican ancestryAgeAggressive behaviorAneuploidyAutomobile DrivingBiological MarkersBiological Response Modifier TherapyBlack PopulationsBlack raceBreast Cancer PatientCancer CenterCaribbean HispanicCaribbean regionCell LineCell SurvivalCellsCentrosomeCessation of lifeChromosomal InstabilityChromosomesClinicalCopy Number PolymorphismCubanDNA sequencingDataDiagnosisDominicanE-CadherinEstrogensEthnic OriginEuropeanFunctional disorderGene Expression ProfileGenerationsGenetic TranscriptionGenomeGenomicsGoalsGrowthHispanicIncidenceIndividualLaboratoriesLatina PopulationLatinoLinkMalignant NeoplasmsMammary NeoplasmsMeasuresMesenchymalMessenger RNAMitoticMolecularNatureNeoplasm MetastasisNot Hispanic or LatinoOrganoidsOutcomePathologyPathway interactionsPatient-derived xenograft models of breast cancerPatientsPhosphorylationPhosphotransferasesPrevalencePrincipal InvestigatorProbabilityProgesteronePrognosisPublishingPuerto RicanPuerto RicoRaceRelapseResearch PersonnelRisk FactorsSamplingSignal PathwaySocioeconomic StatusSurvival RateTBK1 geneTestingThe Cancer Genome AtlasTissue MicroarrayTransitional CellTreatment outcomeTumor MarkersTumor stageUnited StatesVimentinWomanaurora kinasebiobankblack womenbreast cancer survivalcancer cellcancer health disparitycombinatorialepithelial to mesenchymal transitionexperimental studyhigh riskimprovedinhibitormalignant breast neoplasmmigrationmortality risknovelnovel therapeutic interventionoverexpressionpatient derived xenograft modelpreventracial and ethnicracial and ethnic disparitiesreceptorrecruitresponseslugstemnesssurvival outcometranscription factortranscriptome sequencingtriple-negative invasive breast carcinomatumortumor growthtumor heterogeneitytumor initiationwhole genome
项目摘要
Non-Hispanic black (NHB) and Hispanic/Latino (H/L) women in the United States (US) have higher probabilities
of breast cancer-related death than non-Hispanic white (NHW) women. H/L women from the Caribbean (C-H/L,
Puerto Rican, Cuban and Dominican) and black H/L are at an even higher risk of death than H/L from other
regions and white H/L. This higher risk is in part due to NHB and C-H/L with breast cancers being more likely to
be detected at younger ages, with tumors of higher stages and grades, and with triple-negative breast cancers
(ER-PR- and Her2- or TNBC). African ancestry combined with less of the protective European genome greatly
influences these risk factors in NHB and C-H/L women (on average having 79% and 27% African genomic
contribution, respectively). Centrosome amplification-driven mitotic dysfunction leading to chromosome
instability (CIN) and aneuploidy may also contribute to metastasis and poor clinical outcomes of these TNBC
patients. The Co-PIs published that the centrosome/mitotic kinases TTK, NEK2, and TBK1 generate CA/CIN
and that TTK and NEK2 drive the epithelial to mesenchymal transition (EMT). Preliminary data indicates that
TTK, NEK2, and TBK1 mRNAs are dysregulated in NHB and TNBCs, and are overexpressed in breast tumors
from C-H/L. Also, by using a novel NCI-BMAP3 region breast cancer tissue microarray (TMA) containing
samples from NHW, NHB, and C-H/L women, the Co-PIs found that TTK and pTBK1 are overexpressed in TNBC
and TTK correlates with EMT in TNBC. Inactivating TTK or TBK1 restored Rb in TNBC cells, suggesting it can
restore Palbociclib responses. Co-inactivating TTK and TBK1 in TNBC cells reduced the levels of
centrosome/mitotic regulators and EMT markers, and co-inactivating TTK/TBK1 or TTK/NEK2 significantly
reduced the migration and invasion of TNBC. The study team hypothesizes that TTK, NEK2, and TBK1
dysregulation in C-H/L and NHB women with breast cancer (BC) is dictated by African ancestry and contributes
to their poor survival outcomes by driving cancer cell survival and early metastasis. To test this hypothesis, the
team proposes the following Specific Aims: (1) Investigating signaling pathways linking mitotic kinases to early
metastasis and poor prognosis of non-Hispanic black (NHB), Caribbean Hispanic/Latino (C-H/L), and
Hispanic/Latino (H/L) women with breast cancer. The team will determine if RNA expression signatures and copy
number variations correlate with the expression of mitotic kinases with EMT markers, and survival outcomes,
using RNA and DNA seq done by the ORIEN consortium and a novel TMA developed by the Puerto Rico
Biobank. (2) To address how co-inactivation of mitotic kinases suppresses the mesenchymal state, metastasis,
and restores Palbociclib responses in TNBC cells. This will be addressed by single and combinatorial inhibition
of TTK, NEK2, and TBK1 in primary cell lines and PDX models of TNBC from NHB and H/L women with breast
cancer. Results from the proposed experiments will help reduce ethnic/racial breast cancer disparities by
identifying actionable targets (TTK, NEK2, TBK1, and other novel kinases found in Aim 1) against the aggressive
growth and early metastatic progression in NHB and H/L women with TNBC.
非西班牙裔黑人(NHB)和西班牙裔/拉丁裔(H/L)妇女在美国(US)有更高的概率
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 }}
William Douglas Cress其他文献
William Douglas Cress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('William Douglas Cress', 18)}}的其他基金
Targeting centrosome‐mitotic kinases as a novel therapeutic approach against breast cancers in Hispanic/Latinas.
靶向中心体有丝分裂激酶作为治疗西班牙裔/拉丁裔乳腺癌的新方法。
- 批准号:
10705160 - 财政年份:2022
- 资助金额:
$ 48.32万 - 项目类别:
Cancer Research Workforce Development in FAIR Artificial Intelligence and Machine Learning
FAIR 人工智能和机器学习中的癌症研究劳动力发展
- 批准号:
10405929 - 财政年份:2019
- 资助金额:
$ 48.32万 - 项目类别:
相似海外基金
Re-igniting Windrush folk song and stories to improve African-Caribbean mental health disparities
重新点燃 Windrush 民歌和故事,改善非洲和加勒比地区的心理健康差异
- 批准号:
AH/X012387/1 - 财政年份:2023
- 资助金额:
$ 48.32万 - 项目类别:
Research Grant
Development and implementation of peer-facilitated decision-making and referral support to increase uptake and adherence to HIV pre-exposure prophylaxis in African Caribbean and Black communities in Ontario
制定和实施同行协助决策和转介支持,以提高非洲加勒比地区和安大略省黑人社区对艾滋病毒暴露前预防的接受和依从性
- 批准号:
491109 - 财政年份:2023
- 资助金额:
$ 48.32万 - 项目类别:
Fellowship Programs
Development and implementation of peer-facilitated decision-making and referral support to increase uptake and adherence to HIV pre-exposure prophylaxis in African Caribbean and Black communities in Ontario
制定和实施同行协助决策和转介支持,以提高非洲加勒比地区和安大略省黑人社区对艾滋病毒暴露前预防的接受和依从性
- 批准号:
493049 - 财政年份:2023
- 资助金额:
$ 48.32万 - 项目类别:
Optimizing the vaginal microbiome In African, Caribbean and other Black women from Toronto, Canada: defining clinical endpoints and community priorities
优化来自加拿大多伦多的非洲、加勒比和其他黑人女性的阴道微生物组:确定临床终点和社区优先事项
- 批准号:
494152 - 财政年份:2023
- 资助金额:
$ 48.32万 - 项目类别:
Operating Grants
Strengthening community capacity for HIV prevention and care among African Caribbean and Black (ACB) women in Ontario: An interdisciplinary community-based participatory research initiative
加强安大略省非洲加勒比和黑人 (ACB) 妇女艾滋病毒预防和护理的社区能力:一项基于社区的跨学科参与性研究计划
- 批准号:
463487 - 财政年份:2022
- 资助金额:
$ 48.32万 - 项目类别:
Operating Grants
A-AIDS-2022-01037 and titled "Because she cares: Using spoken word films as a performance-educational tool to catalyze discussion around Canadian AASO employment as (un)caring work for African, Caribbean and Black women living with HIV”
A-AIDS-2022-01037,标题为“因为她关心:使用口语电影作为表演教育工具来促进围绕加拿大 AASO 就业的讨论,作为对感染艾滋病毒的非洲、加勒比和黑人妇女的(非)关怀工作”
- 批准号:
467867 - 财政年份:2022
- 资助金额:
$ 48.32万 - 项目类别:
Implementing Client-Centered Care Coordination to Enhance Equity in the HIV Prevention Impact of PrEP among African, Caribbean and Black Communities in Toronto: A Community-Academic Partnership
实施以客户为中心的护理协调,以增强多伦多非洲、加勒比和黑人社区中 PrEP 艾滋病毒预防影响的公平性:社区学术伙伴关系
- 批准号:
467754 - 财政年份:2022
- 资助金额:
$ 48.32万 - 项目类别:
Operating Grants
Exploring the Lived Experiences of African, Caribbean and Black Digital Health Users and their Perceptions of Trust: A Qualitative Study
探索非洲、加勒比和黑人数字健康用户的生活经历及其对信任的看法:一项定性研究
- 批准号:
486192 - 财政年份:2022
- 资助金额:
$ 48.32万 - 项目类别:
Studentship Programs
Acceptability of HIV/STBBI Dried Blood Spot Testing Among African, Caribbean, and Black Communities in Manitoba
马尼托巴省非洲、加勒比和黑人社区对 HIV/STBBI 干血斑检测的接受度
- 批准号:
486104 - 财政年份:2022
- 资助金额:
$ 48.32万 - 项目类别:
Studentship Programs
Strengthening the capacity of healthcare providers to reduce the impact of COVID-19 on African, Caribbean, and Black communities in Ontario
加强医疗保健提供者的能力,减少 COVID-19 对安大略省非洲、加勒比和黑人社区的影响
- 批准号:
459182 - 财政年份:2021
- 资助金额:
$ 48.32万 - 项目类别:
Operating Grants














{{item.name}}会员




