PERSONALIZED THERAPY FOR p16-DEFICIENT MELANOMA
PERSONALIZED THERAPY FOR p16-DEFICIENT MELANOMA
批准号:
9933633
负责人:
Romi Gupta
金额:
$7.43万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-08-01 至 2020-07-31
关键词:
Affinity ChromatographyAreaBiochemical GeneticsCDKN2A geneCell Culture TechniquesCell CycleCellsCessation of lifeClinicalCombined Modality TherapyComplementDataDiseaseDoxycyclineEpigenetic ProcessGene Expression ProfilingGenesGeneticGenetic Predisposition to DiseaseGenetic TranscriptionGenetic studyGenomeGenomic approachGrowthHumanImmunotherapyMaintenanceMass Spectrum AnalysisMediatingMedicalMelanoma CellMetastatic MelanomaMolecularMutationNeoplasm MetastasisOrganPathogenesisPathway interactionsPatientsPharmacologyPhosphotransferasesProteinsProteomicsPublic HealthRNA InterferenceRNA interference screenRegulationRoleSkin CancerTestingThe Cancer Genome AtlasTherapeuticTumor Suppressor ProteinsTumor-Suppressor Gene InactivationUnited Statesbasecancer cellcancer typeeffective therapyexperimental studyfunctional genomicsimprovedin vivoin vivo Modelinhibitor/antagonistinnovationknock-downmelanomamouse modelnovelpersonalized medicineresponsesmall hairpin RNAsmall molecule inhibitortranscription factortranscriptometumortumor growth
中文摘要
项目总结
英文摘要
Project Summary
Melanoma account for over 10,000 deaths annually in the United States alone and current therapies for
advanced-stage melanoma do not provide durable clinical benefit. Therefore, improved molecular
understanding of melanoma is essential for developing effective therapies. According to The Cancer Genome
Atlas (TCGA) melanoma data over 45% melanoma lack tumor suppressor p16. However, there is no specific
personalized treatment option available for p16-deficient melanoma. Therefore, we performed an innovative
large-scale druggable genome RNAi screen and identified Cell division cycle 7 (CDC7) kinase as a candidate
that is necessary for the survival of p16-deficient melanoma. shRNA-induced knockdown of CDC7 inhibited
p16-deficient melanoma tumors and metastases in vivo. Our central hypothesis is that p16-deficient
melanoma depends upon CDC7 for their survival and CDC7 inhibition will be of therapeutic value for treating
p16-deficient melanoma. The overall objective is to determine the effect of genetic and pharmacological
inhibition of CDC7 on melanoma tumor growth and metastasis and understand why CDC7 is necessary for
p16-deficient melanoma. Specifically, in Aim 1, we will determine the effect of genetic and pharmacological
inhibition of CDC7 on melanoma tumor growth and metastasis. To this end, will determine the role of CDC7 in
tumor growth and metastasis in the context of p16-deficiency. Additionally, using XL413, a small molecule
inhibitor of CDC7, alone or in combination with BRAFV600E inhibitor vemurafenib (for melanoma co-harboring
both BRAFV600E mutation and p16-deficiency), we will determine if pharmacological inhibition of CDC7 alone
or in combination with BRAFV600E inhibitors can be employed to effectively treat p16-deficient melanoma in
vivo. The experimental approach will utilize mouse models of melanoma tumor growth and metastasis and will
utilize established and melanoma patient-derived short-term melanoma cultures available from Yale SPORE in
Skin Cancer. In Aim 2, we will determine why CDC7 is necessary for the survival of p16-deficient melanoma.
Using transcriptome-wide gene expression profiling and Tandem Affinity Purification and mass spectrometry-
based proteomics approaches, we find that the p16-deficient melanoma cells show activation of Unfolded
Protein Response (UPR) pathway and that CDC7 maintains the activity of UPR pathway potentially via
transcription factor HOXA1 to promote melanoma tumor growth and metastasis. Therefore, we will determine
how CDC7 regulates UPR pathway via HOXA1 in p16-deficient melanoma cells. Additionally, we will test
whether CDC7-loss induced tumor growth and metastasis inhibition of p16-deficient melanoma cells can be
rescued by restoring HOXA1 expression and the UPR pathway activity. Collectively, we expect to uncover a
novel CDC7-driven druggable genetic vulnerability pathway that can be targeted for effective personalized
therapy of p16-deficient melanoma, including for highly aggressive metastatic melanoma.
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会议论文
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依托单位:
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依托单位: