Longitudinal therapeutic monitoring of colorectal cancer patients using exosome-based liquid biopsies
Longitudinal therapeutic monitoring of colorectal cancer patients using exosome-based liquid biopsies
批准号:
10197832
负责人:
Scott Kopetz
金额:
$66.4万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-01 至 2023-06-30
关键词:
BioinformaticsBiologicalBiological AssayBiological MarkersBiologyBiometryBiopsyBloodBlood CirculationCLIA certifiedCell CommunicationCell LineCell physiologyCell surfaceCellsClassificationClinicalClinical TrialsCollaborationsColorectal CancerComputational BiologyConsensusDNADataDevelopmentDiseaseDisease modelDistantEpidermal Growth Factor ReceptorFrequenciesGenetic TranscriptionGenomicsGoalsHistonesImmunosuppressionKRAS2 geneLaboratoriesLengthLettersLipidsMalignant NeoplasmsMass Spectrum AnalysisMedical OncologyMembraneMembrane ProteinsMethodologyModelingMolecularMolecular WeightMonitorMonitoring Clinical TrialsMutationNeoplasm Circulating CellsNucleic AcidsOncologistOperative Surgical ProceduresOrganoidsPathologistPathologyPatientsPeptide VaccinesPeptidesPerformancePlasmaProteinsProteomicsRNARecurrenceReproducibilityResectedResidual NeoplasmResistanceSamplingSeriesSiteSolid NeoplasmSurfaceTechnologyTextTherapeuticTissue SampleTissuesTranscriptTranslatingTranslationsTumor DebulkingTumor TissueTumor VolumeUltracentrifugationVisceralWorkactionable mutationbasebioinformatics toolbiomarker discoverycancer cellcancer genomeclinical translationcohortcolon cancer patientsexosomegenomic profilesimmunotherapy trialsinnovationliquid biopsymeetingsmetastatic colorectalmicrovesiclesmolecular diagnosticsmolecular markermolecular subtypesmultidisciplinaryneoantigensnext generation sequencingpreservationprospectiveresponsestandard of caretherapy resistanttooltranscriptometranscriptome sequencingtranscriptomicstreatment stratificationtumortumor microenvironmenttumor progressionvalidation studies
中文摘要
项目摘要及相关性:
英文摘要
Project Summary and Relevance:
Exosomes are bi-layered lipid microvesicles containing DNA, RNA and proteins, which have emerged as an
important avenue for cell-cell communication in cancer. Our team has performed pioneering studies on the utility
of circulating exosomes for genomic and transcriptomic profiling of visceral cancers that are challenging to
sample longitudinally. Specifically, we have demonstrated the remarkable integrity of the nucleic acid cargo
(exoDNA and exoRNA) contained within exosomes, which makes them readily amenable to next generation
sequencing (NGS). The objective of this proposal is to establish the utility of liquid biopsies that enrich for high
quality exosomes as a platform for therapeutic stratification and disease monitoring in advanced colorectal
cancer (CRC). In Aim 1 will meticulously evaluate the most appropriate methodology for reproducible and
sensitive isolation of circulating exosomes from metastatic CRC patients using gradient ultracentrifugation versus
two of the most commonly used commercial kits. We will develop perform rigorous biological and technical
reproducibility assays on the isolated exosomes and nucleic acid cargo that will develop standards necessary
for translation of exosomal-based “liquid biopsy” to a clinical molecular diagnostics laboratory (MDL). We will
also perform mass spectrometry-based proteomic profiling of exosomes isolated from a panel of CRC organoid
models versus control organoids and cell lines, in order to identify the surface proteins (“surfaceome”) present
on CRC-derived exosomes. The surfaceome data will serve as an invaluable tool for enrichment of cancer-
specific exosomes in low-volume tumor settings, such as minimal residual disease monitoring. In Aim 2, we will
compare targeted mutation panel and copy number profiles of tissue samples in patients undergoing surgical
debulking for metastatic (m)CRC, with that of corresponding plasma exoDNA-derived profiles. The remarkable
preservation of exoRNA within exosomes will allow us to perform RNA-Seq and compare the consensus
molecular subtype (CMS) classification obtained by shed exosomes versus metastatic tissues. Finally, in Aim
3, we will longitudinally monitor cohorts of surgically resected CRC patients, or mCRC patients on two
prospective clinical trials, using exosomes as a molecular tool for identifying disease recurrence and emergence
of treatment resistance, respectively. The first trial will evaluate for emergence of low frequency KRAS mutations
and other secondary drivers of resistance to EGFR-based therapies. The second trial is an immunotherapy trial
of multivalent peptide vaccine, where exoRNA data will also be used to predict, and then monitor, expressed
neoantigens in mCRC samples, using bioinformatics tools we have developed for mapping transcript data to
HLA-presented peptides on the cancer cell surface. The long-term goal of these studies is to generate the
compendium of standards and assays needed for successful translation of exosomes as a liquid biopsy platform
to the clinical realm.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
MDACC-PREDICT
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批准号:10266195
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项目类别:
-
资助金额:$67.05万
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财政年份:2020
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负责人:Scott Kopetz
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依托单位:
MDACC-PREDICT
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批准号:10253153
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项目类别:
-
资助金额:$66.99万
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财政年份:2020
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负责人:Scott Kopetz
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依托单位:
Career Enhancement Program
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批准号:10415973
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项目类别:
-
资助金额:$15.27万
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财政年份:2019
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负责人:Scott Kopetz
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依托单位:
MD Anderson Cancer Center SPORE in Gastrointestinal Cancer
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批准号:10226083
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项目类别:
-
资助金额:$198.74万
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财政年份:2019
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负责人:Scott Kopetz
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依托单位:
Administrative Core
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批准号:10226084
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项目类别:
-
资助金额:$24.84万
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财政年份:2019
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负责人:Scott Kopetz
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依托单位:
MD Anderson Cancer Center SPORE in Gastrointestinal Cancer
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批准号:10415964
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项目类别:
-
资助金额:$221.13万
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财政年份:2019
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负责人:Scott Kopetz
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依托单位:
Administrative Core
-
批准号:10415965
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项目类别:
-
资助金额:$26.82万
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财政年份:2019
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负责人:Scott Kopetz
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依托单位:
Career Enhancement Program
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批准号:10226092
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项目类别:
-
资助金额:$24.84万
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财政年份:2019
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负责人:Scott Kopetz
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依托单位:
Colorectal Cancer Molecular Subtype Assay Development and Validation
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批准号:10463838
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项目类别:
-
资助金额:$34.1万
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财政年份:2018
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负责人:Scott Kopetz
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依托单位:
Colorectal Cancer Molecular Subtype Assay Development and Validation
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批准号:9789655
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项目类别:
-
资助金额:$16.37万
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财政年份:2018
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负责人:Scott Kopetz
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依托单位:
Longitudinal therapeutic monitoring of colorectal cancer patients using exosome-based liquid biopsies
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批准号:10439595
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项目类别:
-
资助金额:$65.07万
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财政年份:2018
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负责人:Scott Kopetz
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依托单位:
Colorectal Cancer Molecular Subtype Assay Development and Validation
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批准号:10334569
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项目类别:
-
资助金额:$29.71万
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财政年份:2018
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负责人:Scott Kopetz
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依托单位:
Project 2: Building Combinatorial Therapies against KRAS-mutant Colorectal and Pancreatic Cancer
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批准号:10242651
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项目类别:
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资助金额:$12.0万
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财政年份:2017
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负责人:Scott Kopetz
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依托单位:
Project 2: Building Combinatorial Therapies against KRAS-mutant Colorectal and Pancreatic Cancer
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批准号:10681975
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项目类别:
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资助金额:$9.65万
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财政年份:2017
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负责人:Scott Kopetz
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依托单位:
Project 2: Building Combinatorial Therapies against KRAS-mutant Colorectal and Pancreatic Cancer
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批准号:10242643
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项目类别:
-
资助金额:$21.81万
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财政年份:2017
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负责人:Scott Kopetz
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依托单位:
Stress Signaling Pathways and Resistance in Colorectal Cancer
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批准号:8420658
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项目类别:
-
资助金额:$31.61万
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财政年份:2013
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负责人:Scott Kopetz
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依托单位:
Stress Signaling Pathways and Resistance in Colorectal Cancer
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批准号:8606445
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项目类别:
-
资助金额:$30.66万
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财政年份:2013
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负责人:Scott Kopetz
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依托单位:
Src inhibition in Colorectal Cancer
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批准号:7570789
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项目类别:
-
资助金额:$13.48万
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财政年份:2008
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负责人:Scott Kopetz
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依托单位:
Src inhibition in Colorectal Cancer
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批准号:7694304
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项目类别:
-
资助金额:$13.48万
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财政年份:2008
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负责人:Scott Kopetz
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依托单位:
Src inhibition in Colorectal Cancer
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批准号:8320755
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项目类别:
-
资助金额:$13.48万
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财政年份:2008
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负责人:Scott Kopetz
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依托单位:
海外基金