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The role of PGC1beta and ERRalpha as novel targets for therapy in colorectal cancer

The role of PGC1beta and ERRalpha as novel targets for therapy in colorectal cancer
PGC1beta 和 ERRalpha 作为结直肠癌治疗新靶点的作用
批准号:
10164730
负责人:
Kurt Fisher
金额:
$23.76万
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:
2018-07-02 至 2023-06-30
关键词:
5&apos-AMP-activated protein kinaseAdipose tissueAnimal ModelBiogenesisBiologyBrainBreastBrown FatCancer EtiologyCancer cell lineCecumCessation of lifeColonColonic NeoplasmsColorectal AdenocarcinomaColorectal CancerCyclic AMP-Dependent Protein KinasesDataDevelopmentDevelopment PlansDiseaseDistantDistant MetastasisEGF geneERR1 proteinEpidermal Growth Factor ReceptorEpithelial CellsEstrogen Receptor alphaEthicsEventFacultyGenderGene ExpressionGenesGenetic TranscriptionGrowthHeartHomeostasisHumanIn VitroKRAS2 geneKnock-outKnowledgeLeadershipLigand BindingLigand Binding DomainLigandsLiverMaintenanceMalignant NeoplasmsMass Spectrum AnalysisMentorsMentorshipMetabolicMetabolismMetastatic Neoplasm to the LiverMitochondriaModelingMolecularMusMuscleMutateMutationNeoplasm MetastasisNormal CellNuclear Orphan ReceptorOncogenicPPAR gammaPathway interactionsPatient-Focused OutcomesPatientsPhysiciansPlayPost-Translational Protein ProcessingPrimary NeoplasmPrognosisProtein FamilyProtein KinaseProteinsPublicationsRegulationResearchResearch TrainingResistanceResponse ElementsRoleScientistSignal TransductionSkeletal MuscleSmall Interfering RNASolid NeoplasmSurvival RateTestingTherapeuticTherapeutic IndexTissuesTrainingTranscription CoactivatorUnited StatesWomanWorkXenograft ModelXenograft procedurebioinformatics toolcareer developmentcell growthcolon cancer cell linecross reactivitydelta proteindesignestrogen-related receptorgenome-widehuman tissueimplantationimprovedin vivoinhibitor/antagonistmembermenmetastatic colorectalmouse modelmutantnew therapeutic targetnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsoverexpressionpromoterras Proteinsras-Related G-Proteinsside effectskillstargeted treatmenttranscription factortranslational impacttreatment strategytumortumor growthtumor metabolismtumorigenesis

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Abstract Significance: This proposal has the potential to impact a large number of patients since colorectal cancer (CRC) is the 3rd leading cause of cancer deaths in both genders. K-Ras is mutated in approximately 40% of all CRCs and this mutation makes tumors resistant to EGFR-targeted therapies. Our studies aim to develop novel strategies for treatment of tumors with K-Ras mutations. Additionally, we propose that our treatment strategies will have a high therapeutic index, since we are targeting proteins that are expendable for normal growth, but required for malignancy. We also anticipate that our findings will be applicable to other tumors with mutant Ras proteins, which constitute up to 30% of all human malignancies. Background: We have determined that 5' AMP-activated protein kinase (AMPK), peroxisome proliferator- activated receptor gamma coactivator 1-beta (PGC1β), and estrogen-related receptor alpha (ERRα) are novel regulators of tumor metabolism in K-Ras mutant CRCs. PGC1β is a transcriptional co-activator and ERRα is a transcription factor that are present in highly metabolic tissues, such as heart, skeletal muscle, brain and brown adipose tissue, where they interact to transcribe genes involved in metabolism and mitochondrial biogenesis. PGC1β and ERRα are dramatically over-expressed in CRC cell lines and human liver metastases compared to non-transformed human colon epithelial cells (HCECs) and normal human colon tissue, respectively. AMPK, a critical regulator of energy homeostasis, is a potent regulator of PGC1β, ERRα, and tumor survival. Research Plan: In this application, we present preliminary data on the critical role of AMPK, PGC1β, and ERRα as novel regulators of tumor metabolism and survival in K-Ras mutant CRCs and we hypothesize that these are promising targets for the development of novel treatment strategies because they are expendable for normal cell growth. To test this hypothesis, first, we will examine the role of PGC1β and ERRα downstream effector Ras-related GTP-binding protein D (RagD), a positive regulator of mTORC1 signaling and tumor growth. Second, we will characterize the critical regulatory role of AMPK on PGC1β activity. Lastly, we will assess the role of PGC1β, ERRα, and an ERRα inhibitor in metastatic disease using the orthotopic cecal implantation mouse model of metastasis. This proposal will advance our knowledge of these underexplored metabolic effectors that are required for K-Ras mutant CRCs and have the potential for the development of several types of novel therapeutics. Career Development: I have worked closely with my mentors to create a scientific and career development plan designed to help me transition to independence as a physician-scientist. Specifically, I will gain valuable training in metabolic regulation of cancer growth, models of metastasis, leadership skills, grantsmanship, and ethical research. My mentorship committee consists of outstanding faculty members with expertise in mentoring junior faculty members, CRC research, and training of physician-scientists.
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Novel Mechanisms of Inhibiting Transcriptional Coactivators for Anti-Cancer Therapy in Colorectal Cancer
The role of PGC1beta and ERRalpha as novel targets for therapy in colorectal cancer
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