Targeting Microtubule Associated Protein Tau in Ovarian Carcinoma to Increase Efficacy of Paclitaxel
Targeting Microtubule Associated Protein Tau in Ovarian Carcinoma to Increase Efficacy of Paclitaxel
批准号:
9811849
负责人:
Maria V. Barbolina
金额:
$20.35万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-07-01 至 2021-06-30
关键词:
AddressAlzheimer&aposs DiseaseApoptoticCancer EtiologyCause of DeathCell Culture TechniquesCell LineCellsCessation of lifeClinicClinicalClinical TrialsCombination Drug TherapyDataDementiaDiseaseDown-RegulationDrug EffluxDrug InteractionsDrug KineticsDrug TargetingEpithelialEpithelial ovarian cancerGenerationsGoalsImpairmentIn VitroInvestigationLaboratoriesLinkMAPT geneMalignant Epithelial CellMalignant Female Reproductive System NeoplasmMalignant NeoplasmsMalignant neoplasm of ovaryModelingMolecularMotivationNatureNeoplasm MetastasisNeurodegenerative DisordersNeurosciencesOperative Surgical ProceduresOutcomeOvarian CarcinomaOvarian Serous AdenocarcinomaPaclitaxelParalysedPatientsPharmaceutical PreparationsPharmacology and ToxicologyPhasePhenotypePlatinumPlatinum CompoundsPre-Clinical ModelRecurrenceRefractoryRelapseResearchResistanceSeriesSpecimenTauopathiesTestingTherapeuticTubulinTumor BurdenUnited States Food and Drug AdministrationUniversitiesUp-RegulationValidationWomanXenograft Modelbasechemosensitizing agentchemotherapyclinical developmentcytotoxicityefflux pumpexperimental studyin vivoinhibitor/antagonistmortalitypreclinical studypreventresponsetargeted agenttau Proteinstau expressiontaxane
中文摘要
摘要
英文摘要
ABSTRACT
Mortality from epithelial ovarian carcinoma has not changed significantly over the past century. This disease still
remains the deadliest gynecologic malignancy and the fifth leading cause of cancer death in women. The
metastasis is the main cause of death from this morbid disease, and one of the key problems preventing
successful treatment is chemotherapy resistance. The long-term goal of the studies in our laboratory is to
characterize molecular mechanisms regulating ovarian carcinoma metastasis and its recurrent chemotherapy-
resistant phenotype. The objective of the study outlined in this proposal is to determine the efficacy of targeting
the microtubule-associated protein tau to increase paclitaxel response.
Patients with advanced ovarian carcinoma are typically treated with surgery and a combination chemotherapy
containing a taxane (most commonly, paclitaxel) and a platinum agent. Furthermore, paclitaxel is used as a
second line agent in relapsed platinum-refractory epithelial ovarian cancer. Previous studies have linked several
different molecular mechanisms with paclitaxel resistance; however, so far, there are no clinically used strategies
to overcome these mechanisms. More recent previous studies, including those from our lab, have linked
expression of tau with resistance to paclitaxel in specimens of serous ovarian carcinoma. Our data suggest that
the number of tau-positive cases in the metastasis significantly increases compared to primary cancer. We have
also demonstrated that downregulation of tau expression in cell culture models synergistically sensitized cells to
paclitaxel. This suggests that strategies to reduce tau levels or its expression could benefit outcomes of the
paclitaxel treatment in metastatic ovarian carcinoma.
Importantly, as aberrant tau has been also associated with a number of neurodegenerative diseases significant
efforts in this field has been made to develop inhibitors and drugs targeting tau to treat these debilitating
conditions. However, it remains to be established whether tau-based drugs and inhibitors could be used to
increase paclitaxel sensitivity in ovarian carcinoma. We are partnering with a neuroscientist, Dr. Peter Penzes
(Northwestern University) to determine the efficacy of tau inhibitors in preclinical models of ovarian cancer.
In this application we hypothesize that drugs targeting tau, which were originally developed to treat
neurodegenerative diseases, will synergize with paclitaxel in increasing its cytotoxicity and reducing clone
formation of HGSOC cells, resulting in significantly reduced tumor burden in vivo. To test this hypothesis, we
propose these specific aims: 1) to validate the efficacy of the combination of tau-based therapeutics and
paclitaxel in pre-clinical models of HGSOC, and 2) to validate tau-based therapeutics in their efficacy to re-
sensitize paclitaxel-resistant ovarian carcinoma to the paclitaxel treatment. The proposed experiments will be
conducted using preclinical models of high grade serous ovarian carcinoma, including cell culture and xenograft
models.
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会议论文
Role of the Fractalkine Signaling in EOC
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批准号:8165146
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项目类别:
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资助金额:$20.3万
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财政年份:2011
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负责人:Maria V. Barbolina
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依托单位:
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批准号:8307540
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项目类别:
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