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Efficacy and Safety of a Novel, Implantable Drug-eluting Film in Sarcoma

Efficacy and Safety of a Novel, Implantable Drug-eluting Film in Sarcoma
新型植入式药物洗脱膜治疗肉瘤的功效和安全性
批准号:
9206159
负责人:
Yolonda L Colson
金额:
$40.76万
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:
2016-01-14 至 2019-11-30
关键词:
3-DimensionalAbdomenAddressAdjuvant TherapyAnatomyAnimal ModelAnimalsAntineoplastic AgentsAortaArchitectureAreaBackBedsBundlingCell CycleCell Cycle KineticsCell DeathCell LineCell SurvivalClinicalColonDataDevelopmentDevicesDistantDoseDrug Delivery SystemsDrug resistanceExcisionExposure toExternal Beam Radiation TherapyFailureFilmG1 ArrestG2/M ArrestGoalsHandHistologyHumanImageImplantIn VitroIncidenceInferior vena cava structureInvadedLeftLeft kidneyLiverMedialMediatingMethodsMicrotubulesModelingMorbidity - disease rateMusNude MiceOperative Surgical ProceduresOrangesPaclitaxelPathway interactionsPatientsPatternPelvisPerioperativePharmaceutical PreparationsPharmacodynamicsPolymersPreventionPublicationsRecurrenceResectedResidual TumorsResourcesRetroperitoneal SpaceRight kidneyRiskS-Phase FractionSafetySamplingSiteSolidStromal NeoplasmStructureSurfaceSurgical ModelsSurgical OncologySurgical marginsSurgical suturesSurvival RateTP53 geneTimeTissue HarvestingTissue imagingTissuesTumor TissueX-Ray Computed TomographyXenograft ModelXenograft procedurebiocompatible polymerbiomacromoleculebiomaterial compatibilitycancer cellchemotherapyclinical practiceflexibilityhealingimplantationimprovedin vivointraperitoneal therapykillingsmortalityneoplastic cellnovelnovel strategiespre-clinicalpreventprofiles in patientsprogramspublic health relevancereconstructionresearch clinical testingresponsesafety and feasibilitysarcomaskillssoft tissuestandard of caresystemic toxicitytumortumor microenvironment

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英文摘要
 DESCRIPTION (provided by applicant): Local recurrence is the most common pattern of failure for retroperitoneal, abdominal, and pelvic (RAP) sarcomas. Despite a macroscopically complete resection, surgical margins are typically positive due to large tumor size and anatomic complexity, resulting in 5-year local recurrence rates of 50% to 90%. Mortality is due to locoregional rather than distant failure and therefore, strategies to improve survival must reduce locoregional failure rates. Trials evaluating perioperative and/or intraoperative external beam radiation therapy, single-dose hyperthermic intraperitoneal chemotherapy, and systemic chemotherapy have failed to demonstrate benefit. We recently developed a novel, flexible, tissue-conforming, biocompatible polymer film (Biomacromolecules, 2012, 13, 406-411) that can be placed intraoperatively over the entire tumor resection bed to slowly elute the chemotherapeutic drug paclitaxel ("Pax-films") locally and kill residual tumor cells. When utilized in our mouse surgical model of recurrent sarcoma, Pax-films markedly increased local tissue paclitaxel levels, avoided systemic toxicity, reduced locoregional recurrence rates, and improved overall survival without healing complications (Annals of Surgical Oncology, 2012, 19, 199-206.). Utilizing an organotypic in vitro culture method that preserves tumor architecture and microenvironment, enables pharmacodynamics profiling of a given tumor's response to chemotherapeutic drug delivery providing the means to predict which specific histologies, or potentially which specific patients, benefit the most from Pax-films. Lastly, we have established mouse xenograft models capable of rapid local tumor recurrence after surgery which allows us to evaluate efficacy of anti-neoplastic therapy against a variety of human sarcomas in vivo. With these skill sets and resources in hand, we can now address the following three specific aims: SPECIFIC AIM 1: Investigate efficacy and pharmacodynamic profiling of the Pax-film response against resected patient-derived sarcomas in vitro. SPECIFIC AIM 2: Define the pharmacodynamic profile and mechanism of action of Pax-films in the prevention of locoregional recurrence of human sarcoma xenografts in vivo. SPECIFIC AIM 3: Assess safety, feasibility, and perioperative morbidity of Pax-film implantation in a pre- clinical large animal model of surgical resection. Successful completion of this proposal will answer the hypothesis that prolonged exposure to paclitaxel-loaded polymer films will: 1) reduce tumor cell viability in vitro for human-derived sarcoma cell lines and patient tumor samples as assessed via organotypic culture; 2) reduce locoregional recurrence rates and improve survival in mouse surgical models of human sarcoma; and 3) prove to be safe and feasible for locoregional drug delivery, achieving high local tissue drug levels with low systemic delivery, when implanted in a large animal along tissue planes and vital structures commonly exposed during clinical extirpative sarcoma surgery.
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Biodegradable, Biocompatible Pressure Sensitive Adhesives
Biodegradable, Biocompatible Pressure Sensitive Adhesives
Supratherapeutic PTX Buttresses Reduce Locoregional Recurrence Rates Following Surgery for Soft Tissue Sarcomas
  • 批准号:
    10670441
  • 项目类别:
  • 资助金额:
    $69.56万
  • 财政年份:
    2022
  • 负责人:
    Yolonda L Colson
  • 依托单位:
Precise tumor targeting with logic CAR circuits
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