Receptor-Targeted Fluorescence-Guided Surgery in Pancreatic Neuroendocrine Tumors
胰腺神经内分泌肿瘤受体靶向荧光引导手术
基本信息
- 批准号:10522096
- 负责人:
- 金额:$ 66.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressBackBindingCancer CenterCanis familiarisCaringCellsChargeChelating AgentsClinicClinicalClinical ResearchClinical TrialsComparative StudyConsensusContractsContrast MediaDataDetectionDevelopmentDocumentationDoseDrug CompoundingDrug DesignDyesEffectivenessExcisionExocrine pancreatic insufficiencyFeedbackFluorescenceFluorescent DyesFreeze DryingGenerationsGoalsGuidelinesHead and Neck CancerHistopathologyHumanImageImage-Guided SurgeryImaging technologyImpairmentIncidenceInjectionsInvestigationInvestigational DrugsInvestigational New Drug ApplicationIslet Cell TumorLabelLeadMalignant neoplasm of ovaryManufacturer NameMediatingMedical OncologistMetastatic Neoplasm to Lymph NodesModelingMolecular TargetMultifocal LesionMusNeoplasm MetastasisNormal tissue morphologyOperating RoomsOperative Surgical ProceduresOrganPancreatectomyPatientsPenetrationPeptide SynthesisPerformancePharmacologyPharmacology and ToxicologyPhasePhase I Clinical TrialsPhase II Clinical TrialsPhase III Clinical TrialsPlayPostoperative PeriodPre-Clinical ModelPreparationProceduresProductionPropertyPublic HealthQuality of lifeRattusRecurrenceResearchRoleSafetySerumSerum ProteinsSignal TransductionSmall IntestinesSolidSomatostatin ReceptorStainsSurgeonSurgical OncologySurgical marginsSynthesis ChemistrySystemic TherapyTactileTestingTissuesToxicologyTranslatingVisualizationWorkXenograft Modelanalogbasecancer therapycontrast imagingcyaninedesigndetection sensitivityefficacy evaluationfirst-in-humanfluorescence-guided surgeryfluorophorefunctional near infrared spectroscopygood laboratory practiceimaging agentimaging approachimaging modalityimprovedin vivoinnovationmanufacturing processminimally invasivemodel developmentmortality riskmultimodalitynovelnuclear imagingpatient derived xenograft modelpatient populationphase I trialpre-clinicalpreclinical safetypreclinical toxicityprimary endpointradiotracerreceptorreceptor bindingsafety studyscale upsecondary endpointsomatostatin analogstandard of caresurgery outcometargeted agenttargeted imagingtheranosticstranslational potentialtumortumor specificitytumor xenograftuptake
项目摘要
PROJECT SUMMARY
The goal of this proposal is to clinically translate a fluorescently labeled contrast agent that improves surgical
outcomes in patients with pancreatic neuroendocrine tumors (pNETs). Surgery is the main treatment option for
these patients and can be curative if tumors are completely removed. However, the inability to accurately identify
pNETs intraoperatively can lead to sub-optimal surgical outcomes and decreased survival. Fluorescence-guided
surgery (FGS) could potentially address this clinical need, but the absence of a molecularly targeted fluorescent
agent has thus far limited its utility in pNETs. Accordingly, our team converted the clinical radiotracer, 66GaDOTA-
TOC, into a fluorescent counterpart that showed highly selective uptake in xenograft models and surgical
biospecimens that express somatostatin receptor subtype 2 (SSTR2). A key drawback of the dye moiety, known
as IR800, is its highly negative charge that leads to non-specific interaction with serum proteins and tissues. As
a result, agent uptake is significant in non-target tissues and leads to reduced image contrast. Zwitterionic (i.e.,
charge-balanced) dyes have been developed to overcome this limitation and have outperformed IR800
counterparts in comparative studies. To evaluate the effects of dye charge on in vivo performance, we replaced
IR800 with the charge-balanced near-infrared fluorescent dye, FNIR-Tag, to produce the second-generation
agent, MMC(FNIR-Tag)-TOC. Our preliminary data showed that MMC(FNIR-Tag)-TOC had significantly lower
background signal than the first-generation agent in nearly all normal tissues along with higher tumor uptake.
The remarkable increase in tumor-to-background ratios suggests excellent potential for intraoperative detection
of SSTR2-expressing tumors and high translational utility as demonstrated in an SSTR2-expressing patient-derived
xenograft (PDX) tumor model and in an orthotopic tumor model that showed excellent correlation
between preoperative nuclear imaging, FGS, and histopathology. We also showed preliminary evidence of safety
in mice and identified a manufacturing process to support agent scale-up. We seek to build on these findings
and propose the following specific aims: (1) implement a manufacturing plan to support IND-enabling studies,
(2) examine preclinical toxicity/pharmacology and complete the required documentation for submission of an
IND application, and (3) conduct a first-in-human phase 1 clinical study in patients with pNETs. To accomplish
our aims, we have formed a strong investigational team that combines the expertise of Dr. Azhdarinia (contact
Pl) in contrast agent development with the expertise of Dr. lkoma (multi-Pl) in surgical oncology. The team is
supported by surgeons from MD Anderson Cancer Center that specialize in treating NETs and medical
oncologists who oversee one of the world's highest-volume NET centers. Successful completion of our aims will
demonstrate feasibility for phase 2/3 studies to evaluate the efficacy of our strategy and will broadly impact the
field by serving as a model for the development of other targeted agents that are suitable for surgical guidance.
项目总结
项目成果
期刊论文数量(0)
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Ali Azhdarinia其他文献
Ali Azhdarinia的其他文献
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{{ truncateString('Ali Azhdarinia', 18)}}的其他基金
Receptor-Targeted Fluorescence-Guided Surgery in Pancreatic Neuroendocrine Tumors
胰腺神经内分泌肿瘤受体靶向荧光引导手术
- 批准号:
10654865 - 财政年份:2022
- 资助金额:
$ 66.21万 - 项目类别:
Development of hybrid somatostatin analogs for surgical guidance
用于手术指导的混合生长抑素类似物的开发
- 批准号:
9268013 - 财政年份:2014
- 资助金额:
$ 66.21万 - 项目类别:
Development of hybrid somatostatin analogs for surgical guidance
用于手术指导的混合生长抑素类似物的开发
- 批准号:
8697203 - 财政年份:2014
- 资助金额:
$ 66.21万 - 项目类别:
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