Multiplexed and dynamically targeted photoimmunotherapy of heterogeneous, chemoresistant micrometastases guided by online in vivo optical imaging of cell-surface biomarkers
由细胞表面生物标志物在线体内光学成像引导的异质性、耐药性微转移的多重动态靶向光免疫疗法
基本信息
- 批准号:10617176
- 负责人:
- 金额:$ 60.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAntibodiesBindingBiological MarkersBiological ModelsCalibrationCancer PatientCancer cell lineCarcinomatosisCell Death InductionCell SurvivalCell membraneCell surfaceCellsChemoresistanceChemosensitizationClinicalComplementComplexCulture TechniquesDepositionDevelopmentDiseaseDisease ResistanceDrug KineticsDrug resistanceEpidermal Growth Factor ReceptorEpithelial ovarian cancerEvolutionFeedbackFluorescenceGenetically Engineered MouseGenotypeGoalsGreater sac of peritoneumHeterogeneityHumanImageImage EnhancementImaging technologyImmunocompetentImmunoconjugatesIn VitroIntestinesLeadLeftMalignant NeoplasmsMeasuresMembraneMethodsMicrometastasisMicroscopeMicroscopicModalityModelingMolecular TargetMonitorMusOperative Surgical ProceduresOptical BiopsyOrganOvarianPatientsPelvic cavity structurePeritonealPharmaceutical PreparationsPhenotypePhototoxicityPolymerase Chain ReactionPopulationPreservation TechniqueProteolysisProtocols documentationReceptor Protein-Tyrosine KinasesRecurrenceRecurrent Malignant NeoplasmRecurrent diseaseRegimenResidual CancersResidual NeoplasmResidual stateResistanceResistance developmentResolutionReverse TranscriptionSalvage TherapySeriesSiteSourceSpecificityTestingTherapeutic AgentsTherapeutic IndexTimeTranslatingTumor BurdenVisualizationWorkXenograft procedureantagonistarmbioimagingcancer cellcancer recurrencecancer stem cellcancer therapychemotherapyclinical imagingimage guidedimage guided therapyimaging agentimaging biomarkerimaging informaticsimaging modalityimaging platformimprovedin vivoin vivo Modelin vivo imagingin vivo optical imagingmicroendoscopemicroendoscopymicroscopic imagingminiaturizeminimally invasivemolecular dynamicsmolecular imagingmortalitymouse modelneoplastic cellnovelnovel strategiesnovel therapeuticsoptical imagingoverexpressionpatient derived xenograft modelpersonalized cancer therapypersonalized medicinephotoimmunotherapyreceptorresponsestandard caretargeted treatmenttherapy resistantthree dimensional cell culturethree-dimensional modelingtomographytreatment optimizationtreatment responsetumortumor heterogeneityuptake
项目摘要
PROJECT SUMMARY
Despite advances in surgery, chemotherapy and targeted therapies, survival of metastatic epithelial ovarian
cancer remains dismal due in part to tumor heterogeneity and residual microscopic disease undetectable by
traditional imaging modalities. This malignancy involves peritoneal carcinomatosis at advanced stages; that is,
extensive tumor studding of the pelvic cavity and its resident organs. To address these “invisible” tumors, we
introduce a series of molecular-targeted and cell-activatable imaging and therapeutic agents integrated with a
newly developed miniaturized microscope for multiplexed molecular imaging in vivo—a cellular-resolution
hyperspectral fluorescence microendoscope—that uniquely enable visualization of microscopic deposits of
tumor cells deep inside the body. The multiplexed biomarker imaging feature is motivated by the critical need
to quantitatively monitor cancer cell phenotypes salient to treatment resistance and escape (e.g., cancer stem
cells are defined by multiple cell-surface biomarkers). In parallel, we have also developed near-infrared
photocytotoxic immunoconjugates (PICs) that target cell membrane molecules overexpressed by cancer cells,
including the epidermal growth factor receptor (EGFR), to create a combined photodynamic and receptor
antagonist therapeutic agent for tumor-targeted, activatable photoimmunotherapy (taPIT). The photodynamic
and fluorescence components become de-quenched (activated) upon cancer cell binding, cellular
internalization and lysosomal antibody proteolysis. This strategy overcomes off-target phototoxicity, including
bowel phototoxicity, the major clinical obstacle for photoactivated treatments in complex sites such as the
pelvic cavity. Here, we build on our prior work that shows the PIC is activated within ovarian micrometastases
with 93% sensitivity and 93% specificity in vivo, in a xenograft mouse model using EGFR overexpressing
human epithelial ovarian cancer cells, enabling accurate recognition of tumors as small as 30 μm and selective
destruction of disseminated peritoneal micrometastases. We propose to further develop this platform to
address tumor heterogeneity and chemoresistant phenotypes lurking within residual tumor deposits, which
represents a critical niche in cancer therapy. Current clinical imaging technologies cannot resolve microscopic
tumor deposits left behind by surgery and chemotherapy, and there are limited treatment options for patients
with recurrent, chemoresistant tumors. We anticipate that this new paradigm for microendoscopy-guided taPIT
will complement current treatment modalities for patients with advanced-stage disease and those receiving
salvage therapies, opening new avenues for personalized medicine. The new capabilities will be applied to
guide dynamically targeted taPIT adaptive to phenotype evolution in response to therapy and for monitoring
treatment response of microscopic residual disease.
项目总结
项目成果
期刊论文数量(0)
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Bryan Quilty Spring其他文献
Bryan Quilty Spring的其他文献
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{{ truncateString('Bryan Quilty Spring', 18)}}的其他基金
Disease-homing light delivery by engineering bioluminescent immune cells for whole body precision photomedicine
通过工程生物发光免疫细胞进行疾病引导光传输,用于全身精准光医学
- 批准号:
10578425 - 财政年份:2023
- 资助金额:
$ 60.44万 - 项目类别:
Multiplexed and dynamically targeted photoimmunotherapy of heterogeneous, chemoresistant micrometastases guided by online in vivo optical imaging of cell-surface biomarkers
由细胞表面生物标志物在线体内光学成像引导的异质性、耐药性微转移的多重动态靶向光免疫疗法
- 批准号:
10358581 - 财政年份:2020
- 资助金额:
$ 60.44万 - 项目类别:
Online monitoring and image-guided treatment of chemoresistant micrometastases
化疗耐药微转移的在线监测和图像引导治疗
- 批准号:
9148171 - 财政年份:2015
- 资助金额:
$ 60.44万 - 项目类别:
Hyperspectral Microendscopy to Monitor VEGF During Pancreatic Cancer Therapy
高光谱显微内窥镜监测胰腺癌治疗期间的 VEGF
- 批准号:
8165997 - 财政年份:2010
- 资助金额:
$ 60.44万 - 项目类别:
Hyperspectral Microendscopy to Monitor VEGF During Pancreatic Cancer Therapy
高光谱显微内窥镜监测胰腺癌治疗期间的 VEGF
- 批准号:
8003695 - 财政年份:2010
- 资助金额:
$ 60.44万 - 项目类别:
Hyperspectral Microendscopy to Monitor VEGF During Pancreatic Cancer Therapy
高光谱显微内窥镜监测胰腺癌治疗期间的 VEGF
- 批准号:
8309787 - 财政年份:2010
- 资助金额:
$ 60.44万 - 项目类别:
Core B: Biological Models, Multiplexed Optical Biopsy, Molecular Pathology, and Biostatistics Core
核心 B:生物模型、多重光学活检、分子病理学和生物统计学核心
- 批准号:
10705164 - 财政年份:1999
- 资助金额:
$ 60.44万 - 项目类别:
Core B: Biological Models, Multiplexed Optical Biopsy, Molecular Pathology, and Biostatistics Core
核心 B:生物模型、多重光学活检、分子病理学和生物统计学核心
- 批准号:
10494489 - 财政年份:1999
- 资助金额:
$ 60.44万 - 项目类别:
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