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Proteogenomic studies aimed at understanding ovarian tumor responses to agents targeting the DNA damage response and translating this knowledge into clinical benefit

Proteogenomic studies aimed at understanding ovarian tumor responses to agents targeting the DNA damage response and translating this knowledge into clinical benefit
蛋白质组学研究旨在了解卵巢肿瘤对针对 DNA 损伤反应的药物的反应,并将这些知识转化为临床益处
批准号:
9271779
负责人:
Michael Birrer
金额:
$150.76万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-06-01 至 2022-05-31
关键词:
AdjuvantAftercareBioinformaticsBiological AssayBiometryCancer BiologyCancer cell lineCell LineCenter for Translational Science ActivitiesClinicClinicalClinical ChemistryClinical DataClinical MarkersClinical OncologyClinical TrialsCollectionCombination Drug TherapyDNA DamageDNA RepairData AnalysesData SetDefectDevelopmentDiagnosisDisease ProgressionDisease ResistanceDrug resistanceEmployee StrikesEpithelialEpithelial ovarian cancerFanconi&aposs AnemiaFundingGenomic approachGenomicsGoalsGynecologic Oncology GroupInvestigational TherapiesKnowledgeLiteratureMalignant Female Reproductive System NeoplasmMalignant neoplasm of ovaryMass Spectrum AnalysisMeasurementMediatingMethodsModelingNeoadjuvant TherapyOperative Surgical ProceduresPathway AnalysisPathway interactionsPatient TriagePatientsPharmaceutical PreparationsPlatinumPlatinum CompoundsPre-Clinical ModelProteinsProteomeProteomicsPurinesRefractoryRefractory DiseaseRelapseResearchResearch DesignResistanceResistance developmentSerousSkatesSpecimenTestingTranslatingTumor DebulkingTyrosineWomanXenograft ModelXenograft procedurealternative treatmentarmbasecancer cellcancer therapycandidate markerchemotherapycrosslinkexperiencegenomic datagenomic profileshomologous recombinationinhibitor/antagonistmeetingsmortalitymultiple reaction monitoringnew therapeutic targetnovel strategiesnovel therapeutic interventionnovel therapeuticsovarian neoplasmpredicting responseprotein biomarkersproteogenomicsrepairedresistance mechanismresponseresponse biomarkerstandard of caretargeted agenttaxanetumortumor progression

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英文摘要
Project Summary/Abstract Epithelial ovarian cancer (EOC), the most lethal gynecological malignancy, is diagnosed in more than 225,000 women worldwide each year, with most patients presenting with advanced-stage, high-grade serous ovarian cancers (HGSOC). Despite improvements in surgical and chemotherapeutic approaches, overall mor- tality has not changed significantly for decades. Standard of care involves surgical debulking plus adju- vant/neoadjuvant combination chemotherapy with platinum compounds and taxanes. Platinum compounds damage DNA by inducing intra- and inter-strand cross-links (ICL) between purine ba- ses. ICL repair depends on both Fanconi anemia and BRCA proteins, which are required for homologous re- combination. EOC is one of the most chemo-sensitive epithelial tumors, with initial response rates of ~75% to platinum-based chemotherapy. The striking platinum sensitivity of EOC tumors is thought to be related to their HRD. Unfortunately, 80-90% of patients suffer relapse and develop drug-resistant disease. Moreover, ~20% of patients have platinum-refractory disease at diagnosis. Thus, there are crucial unmet clinical needs for methods to predict platinum responsiveness of EOCs, and for treatments that can be used either alone or in combination with platinum compounds to overcome resistance. The goals of our PTRC are to enhance our ability to predict which EOCs will respond to DNA-damaging platinum therapy, to understand mechanisms of resistance, and to identify potential new drug targets in resistant disease to point to desperately-needed new therapeutic approaches for these patients. Our Proteogenomic Translational Research Center will perform proteo-genomic analyses of EOC preclini- cal models (patient-derived xenografts and cell lines) pre- and post-treatment with platinum to add to and help prioritize potential predictive protein targets of platinum response that have been implicated in the literature. In our Clinical Arm, we will use targeted multiple reaction monitoring (MRM) mass spectrometry-based assays to quantify potential predictive protein targets in tumor specimens obtained through NCI-funded trials, to test their association with response to therapy. In addition, there is an imperfect and incompletely understood overlap in tumor responses between platinum and PARP inhibitors (PARPi); thus, in an exploratory sub-aim, we will de- termine which proteogenomic correlates of platinum response are also associated with response to PARPi (e.g. based on underlying defects in homologous recombination (HR)-mediated DNA repair).
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Proteomic, Genomic, and Longitudinal Pathways to Ovarian Cancer Biomarker Discovery
  • 批准号:
    10426776
  • 项目类别:
  • 资助金额:
    $8.3万
  • 财政年份:
    2021
  • 负责人:
    Michael Birrer
  • 依托单位:
Validation of a genomic signature that predicts for sub-optimal debulking of epithelial ovarian cancer
  • 批准号:
    10150186
  • 项目类别:
  • 资助金额:
    $9.6万
  • 财政年份:
    2018
  • 负责人:
    Michael Birrer
  • 依托单位:
Proteogenomic studies aimed at understanding ovarian tumor responses to agents targeting the DNA damage response and translating this knowledge into clinical benefit
  • 批准号:
    10602812
  • 项目类别:
  • 资助金额:
    $95.13万
  • 财政年份:
    2017
  • 负责人:
    Michael Birrer
  • 依托单位:
海外基金