Role of polo like kinase 4 in melanomagenesis and melanoma progression
Polo 样激酶 4 在黑色素瘤发生和黑色素瘤进展中的作用
基本信息
- 批准号:10046297
- 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:2018
- 资助国家:美国
- 起止时间:2018-10-01 至 2022-09-30
- 项目状态:已结题
- 来源:
- 关键词:AfghanistanApoptosisArchivesBRAF geneBiologyBiopsyCancer PatientCell Culture TechniquesCell CycleCell Cycle RegulationCell LineCentriolesCentrosomeCessation of lifeChemicalsCiliaClimateDataDefectDermatologicDevelopmentDiagnosisDiagnosticDietDiseaseDisease OutcomeExposure toFemaleGene ChipsGenesGeneticGoalsGrowthGrowth and Development functionHealthcareHospitalsHumanHuman ResourcesIn VitroIncidenceIraqLaboratoriesLeadLiteratureMalignant NeoplasmsMelanoma CellMetastatic MelanomaMiddle EastMilitary PersonnelMissionModelingMolecularMutationNOD/SCID mouseNeoplasmsNevusNude MiceOutcome StudyPLK1 genePatientsPhosphotransferasesPlayProcessProtein-Serine-Threonine KinasesProteinsProteomicsRNA InterferenceRecurrenceResearchResistance developmentRiskRoleS-Phase FractionSamplingSkinSkin CancerSpecimenStressTP53 geneTestingTherapeuticTissue MicroarrayTissuesTransgenic MiceTrimethoprim-SulfamethoxazoleUV Radiation ExposureUnited States Department of Veterans AffairsValidationVeteransWarWorkXenograft procedurealpha Tubulinbasecancer diagnosiscancer therapycell transformationchemotherapygastric cancer cellhigh riskhuman tissueimprovedin vitro Modelin vivoindexinginhibitor/antagonistknock-downliquid crystal polymermalemelanocytemelanomamelanomagenesismilitary veteranmouse modelneoplasm registrynovelnovel diagnosticsnovel strategiesoverexpressionpatient derived xenograft modelpericentrinprognosticprospectiveresponsesenescencesmall moleculesmall molecule inhibitorspectrographstandard of caresuicidaltargeted treatmenttherapy resistanttumortumorigenicultraviolet
项目摘要
SUMMARY:
Melanoma is one of the most aggressive human cancers with approximately 87,110 new melanoma cases
and 9,730 melanoma-related deaths predicted in the U.S. in 2017. Further, melanoma is a significant problem
in Veterans. The US military currently is and has been engaged, in missions all over the world, including
recently, in the Middle East (Iraq and Afghanistan). Many US military personnel, who are deployed to high
ultraviolet (UV) index climates in tropical and subtropical zones are potentially at a higher risk for melanoma.
Further, these personnel are not adequately protected because they possibly have survival priorities other than
avoiding UV exposure. Based on the Veterans Affairs Central Cancer Registry (VACCR), melanoma is among
the five most frequently diagnosed cancers among VA cancer patients.
Unfortunately, the available therapeutic strategies have either failed to achieve >25% response or the
responses are short-lived with developing resistance to therapy. Indeed, recent advances in the understanding
of melanoma biology has led to the development of targeted therapies such as BRAF inhibitors (vemurafenib
and dabrafenib) achieved improvement over chemotherapy for melanomas with BRAF-mutations. However,
even with these new targeted approaches, most of the patients develop resistance, thereby failing to achieve
lasting tumor regression. Therefore, further research is needed to understand the mechanism of melanoma
development and progression. Polo-like kinase 4 (PLK4), a serine/threonine kinase, is the master regulator of
centriole duplication. PLK4 is a low abundance suicidal kinase that is known to autophosphorylate itself to
promote its own destruction to limit centriole duplication once per cell cycle. Based on recent research, PLK4 is
emerging as a potential target for cancer treatment. PLK4 has been suggested to be involved in certain
cancers. Interestingly, overexpression of PLK4 has been shown to result in supernumerary centrosomes and
loss of primary cilia in transgenic mice and gastric cancer cells. Importantly, primary cilia exist in melanocytes
and frequently lost in melanoma. Although limited information is available regarding the potential role of PLK4
in certain cancers, its involvement in melanoma development and progression has not been evaluated. In our
preliminary data, we have found that PLK4 is overexpressed in melanoma cells and human tissues (in a limited
number of specimens studied) and its inhibition via a small molecule inhibitor centrinone B results in a
significant anti-proliferative response in multiple human melanoma cell lines. Thus, based on available
literature and our preliminary data, we propose to test the hypothesis that PLK4 plays a critical role in
melanoma development and progression and could serve as a novel target for melanoma management. The
following specific aims are proposed; 1) to define the role of PLK4 in melanoma development and progression,
employing a tissue microarray (TMA) created from retrospective melanoma tissues from Veteran patients, and
an in vitro cell transformation model; 2) to determine the functional and mechanistic significance of PLK4 in
melanoma (downstream mechanisms and effect on cilia formation), in vitro and in vivo; 3) to determine the
therapeutic significance of PLK4 in melanoma in human-relevant mouse models of melanoma, namely,
Braftm1Mmcm Ptentm1Hwu Tg(Tyr-cre/ERT2)13Bos/BosJ model and patient-derived xenografts (PDX) model. This
may ultimately lead to development of novel diagnostic, prognostic or therapeutic approaches for melanoma.
Since melanoma incidence seems to be higher in the Veteran population and our proposed study aimed at
defining the molecular mechanism of melanoma development may lead to identification of novel strategies for
the management of this deadly neoplasm. Therefore, our proposed work is relevant and significant to the
health care of Veterans and is in line with the mission of the Department of Veteran Affairs.
简介:
项目成果
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Nihal Ahmad其他文献
Nihal Ahmad的其他文献
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{{ truncateString('Nihal Ahmad', 18)}}的其他基金
Combined inhibition of PLK1 and NOTCH for melanoma management
联合抑制 PLK1 和 NOTCH 治疗黑色素瘤
- 批准号:
10481129 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Functional and Therapeutic Significance of PLK4 in Melanoma
PLK4 在黑色素瘤中的功能和治疗意义
- 批准号:
10442947 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Functional and Therapeutic Significance of PLK4 in Melanoma
PLK4 在黑色素瘤中的功能和治疗意义
- 批准号:
10671687 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Role of sirtuin 6 in melanoma development and progression
Sirtuin 6 在黑色素瘤发生和进展中的作用
- 批准号:
10426079 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Role of sirtuin 6 in melanoma development and progression
Sirtuin 6 在黑色素瘤发生和进展中的作用
- 批准号:
10595641 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Role of polo like kinase 4 in melanomagenesis and melanoma progression
Polo 样激酶 4 在黑色素瘤发生和黑色素瘤进展中的作用
- 批准号:
9551225 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Role of polo like kinase 4 in melanomagenesis and melanoma progression
Polo 样激酶 4 在黑色素瘤发生和黑色素瘤进展中的作用
- 批准号:
10421255 - 财政年份:2018
- 资助金额:
-- - 项目类别:
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