Ketorolac and Related NSAIDs for Targeting Rho-family GTPases in Ovarian Cancer
Ketorolac and Related NSAIDs for Targeting Rho-family GTPases in Ovarian Cancer
批准号:
9205393
负责人:
Angela Wandinger-Ness
金额:
$30.3万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-01 至 2018-07-31
关键词:
ActinsAcute PainAdhesionsAnimal ModelAnimal TestingAnimalsBehaviorBindingBiological AssayBioreactorsBreast Cancer PatientCancer PatientCancer RelapseCancer cell lineCell AdhesionCell ProliferationCellsClinical TrialsDataData ElementDecision MakingDevelopmentDiseaseDrug FormulationsDrug KineticsEpithelialEvaluationFDA approvedFamilyGenesGuanine NucleotidesGuanosine Triphosphate PhosphohydrolasesHourHumanIndividualInflammationInformaticsInjection of therapeutic agentIntraperitoneal InjectionsInvestigational DrugsKetorolacMalignant NeoplasmsMalignant neoplasm of ovaryMeasurementMiningModelingMonitorMusNeoplasm MetastasisNon-Steroidal Anti-Inflammatory AgentsNude MiceOntologyOutcomeOutcome MeasureOutcome StudyOvarianPainPathway interactionsPatientsPharmaceutical PreparationsPharmacotherapyPhasePhase II Clinical TrialsPlacebosPopulationPreclinical Drug EvaluationProstaglandin-Endoperoxide SynthasePublishingReadinessRecurrenceRelapseRetrospective StudiesSeriesShelter facilityTestingTherapeuticTimeToxic effectTumor BurdenValidationWorkXenograft ModelXenograft procedurebasecancer stem cellcancer therapycancer typecarboxylatecheminformaticschemotherapyclinically relevantcomparativeenantiomerhuman diseaseimplantationimprovedinhibitor/antagonistinterestmigrationmouse modelneoplastic cellnovelnovel therapeuticsovarian neoplasmoverexpressionpre-clinicalprospectiveresearch studyrhorho GTP-Binding Proteinsspecies differencestem cell nichetherapeutic targettooltumortumor growthtumor xenograftvirtual
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Cheminformatics identification of R-ketorolac as a novel pharmacologic entity with Rho-family GTPase
inhibitory activity for ovarian cancer motivates a two-tiered validation strategy. Preclinical and ex vivo testing
will evaluate repurposed new use of the FDA approved, clinically used [R,S]-ketorolac for ovarian cancer and
R-ketorolac for an Investigational New Drug filing. Rho family GTPases (Rac, Rho and Cdc42) collectively
control cell proliferation, adhesion and migration and are of interest as functional therapeutic targets in
numerous epithelial cancers. A virtual drug screen of -carboxylate containing drugs first predicted the R-
enantiomer of the approved drug [R,S]-ketorolac as a high value, clinically relevant GTPase inhibitor. Prior to
our work, the S-enantiomer was considered the sole active component in the racemic drug formulations, with
selective activity against cyclooxygenases (COX) for mitigating inflammation and acute pain. GTPase activity
measurements demonstrate that R-ketorolac is an allosteric inhibitor of guanine nucleotide binding, while the
S-enantiomer of ketorolac shows little to no activity against GTPases. In cell-based assays, R-ketorolac blocks
Rac1 and Cdc42 activation, actin remodeling and downstream cell adhesion, migration and invasion of human
ovarian cancer cell lines. Human efficacy is supported by both our retrospective study demonstrating
significant survival benefit and our prospective Phase 0 trial. [R,S]-ketorolac administration, has favorable
pharmacokinetic distribution, reduces GTPase activities, and inhibits behaviors associated with invasion and
metastasis in patient tumor cells. Based on our comprehensive published data, we hypothesize that
repurposing [R,S]-ketorolac and development of R-ketorolac as an Investigational New Drug will minimize
ovarian cancer relapse by inhibiting Rac1 and Cdc42 dependent tumor metastasis, and reducing protection in
specialized niches to increase vulnerability to chemotherapy. A series of three aims will validate 1) the benefit
of ketorolac in reducing tumor relapse using an animal xenograft model of tumor recurrence, 2) the impact of
ketorolac on minimizing tumor cell-niche interactions through ex vivo organotypic and bioreactor cultures, and
3) ketorolac/ovarian cancer as a predicted therapeutic/ indication pair. These studies will inform `Go vs. No Go'
decision-making for Phase 2a clinical trial implementation of [R,S] ketorolac and R-ketorolac alone in ovarian
cancer patients. An additional outcome of the studies will be to enhance readiness to submit an FDA
Investigational New Drug filing for R-ketorolac as a new therapy for ovarian cancer to overcome the toxicities
and limitations associated with racemic drug.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Fluorescence Microscopy and Cell Imaging Shared Resource
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批准号:8180650
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项目类别:
-
资助金额:$6.58万
-
财政年份:2010
-
负责人:Angela Wandinger-Ness
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依托单位:
Academic Science Education and Research Training
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批准号:8549630
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项目类别:
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资助金额:$77.46万
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财政年份:2009
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负责人:Angela Wandinger-Ness
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依托单位:
Academic Science Education and Research Training
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批准号:8327102
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项目类别:
-
资助金额:$80.8万
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财政年份:2009
-
负责人:Angela Wandinger-Ness
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依托单位:
Academic Science Education and Research Training
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批准号:8538444
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项目类别:
-
资助金额:$60.23万
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财政年份:2009
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负责人:Angela Wandinger-Ness
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依托单位:
Research Project 3: Dissecting the spatio-temporal coordination of endocytic traf
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批准号:8919390
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项目类别:
-
资助金额:$24.44万
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财政年份:2009
-
负责人:Angela Wandinger-Ness
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依托单位:
Academic Science Education and Research Training
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批准号:7691522
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项目类别:
-
资助金额:$30.78万
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财政年份:2009
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负责人:Angela Wandinger-Ness
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依托单位:
Pathologic Mechanisms of Polycystic Kidney Disease
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批准号:7941657
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项目类别:
-
资助金额:$8.99万
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财政年份:2009
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负责人:Angela Wandinger-Ness
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依托单位:
Academic Science Education and Research Training
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批准号:10248411
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项目类别:
-
资助金额:$104.61万
-
财政年份:2009
-
负责人:Angela Wandinger-Ness
-
依托单位:
Academic Science Education and Research Training
-
批准号:8144802
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项目类别:
-
资助金额:$82.2万
-
财政年份:2009
-
负责人:Angela Wandinger-Ness
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依托单位:
Academic Science Education and Research Training
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批准号:9548263
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项目类别:
-
资助金额:$80.91万
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财政年份:2009
-
负责人:Angela Wandinger-Ness
-
依托单位:
Academic Science Education and Research Training
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批准号:10687063
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项目类别:
-
资助金额:$104.6万
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财政年份:2009
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负责人:Angela Wandinger-Ness
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依托单位:
A Confocal Stereology Microscope for UNM's Fluorescence Microscopy Core
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批准号:7595607
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项目类别:
-
资助金额:$31.23万
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财政年份:2009
-
负责人:Angela Wandinger-Ness
-
依托单位:
Academic Science Education and Research Training
-
批准号:9788952
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项目类别:
-
资助金额:$106.28万
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财政年份:2009
-
负责人:Angela Wandinger-Ness
-
依托单位:
Pathologic Mechanisms of Polycystic Kidney Disease
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批准号:7869485
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项目类别:
-
资助金额:$3.0万
-
财政年份:2009
-
负责人:Angela Wandinger-Ness
-
依托单位:
Academic Science Education and Research Training
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批准号:7933658
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项目类别:
-
资助金额:$58.84万
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财政年份:2009
-
负责人:Angela Wandinger-Ness
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依托单位:
Academic Science Education and Research Training
-
批准号:10468995
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项目类别:
-
资助金额:$106.01万
-
财政年份:2009
-
负责人:Angela Wandinger-Ness
-
依托单位:
Academic Science Education and Research Training
-
批准号:9334276
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项目类别:
-
资助金额:$87.35万
-
财政年份:2009
-
负责人:Angela Wandinger-Ness
-
依托单位:
Research Project 3: Dissecting the spatio-temporal coordination of endocytic traf
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批准号:8767025
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项目类别:
-
资助金额:$29.44万
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财政年份:2009
-
负责人:Angela Wandinger-Ness
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依托单位:
Academic Science Education and Research Training
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批准号:8927012
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项目类别:
-
资助金额:$87.4万
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财政年份:2009
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负责人:Angela Wandinger-Ness
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依托单位:
FAIR Data Competency and Machine Learning Readiness for Biomedical Scientists
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批准号:10406055
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项目类别:
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资助金额:$8.56万
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财政年份:2009
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负责人:Angela Wandinger-Ness
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依托单位:
海外基金