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Click Chemistry-Mediated Surface Protein Assay for Quantifying Subpopulations of Hepatocellular Carcinoma-associated Extracellular Vesicles

Award Number: R01CA277530
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Click Chemistry-Mediated Surface Protein Assay for Quantifying Subpopulations of Hepatocellular Carcinoma-associated Extracellular Vesicles - PROJECT SUMMARY Hepatocellular carcinoma (HCC) accounts for 80-85% of primary liver cancers, and mainly occurs in patients with liver cirrhosis or chronic hepatitis B virus (HBV) infection. Prognosis of HCC is dismal primarily due to advanced stage of disease at diagnosis. Current clinical practice guidelines recommend HCC surveillance by biannual liver ultrasound with/without serum alpha-fetoprotein (AFP) for at-risk patients to achieve the goal of detecting HCC at a curative stage. However, their accuracy remains relevantly low with sensitivity between 60- 70% at a specificity of 90%. As such, novel biomarkers for early detection of HCC are still desperately needed. Extracellular vesicles (EVs) are a heterogeneous group of lipid nanoparticles that are released by all types of cells, and even more so by tumor cells and those cells within tumor microenvironment. Tumor-associated EVs are present in circulation at relatively early stages of disease and are readily accessible across all disease stages. Since the surface proteins of tumor-associated EVs could mirror those of the parental tumor cells and those cells within tumor microenvironment, exploiting the diagnostic potential of HCC-associated EVs’ surface protein signatures as a novel biomarker for early detection of HCC holds great promise to significantly augment the ability of current diagnostic modalities. We propose an HCC EV Surface Protein Assay (SPA) to quantify subpopulations of HCC-associated EVs for detecting early-stage HCC. The proposed HCC EV SPA couples two powerful technologies: Click Chemistry- mediated EV Click Beads for isolating different subsets of HCC-associated EVs, and downstream 4-plex real- time immuno-PCR for quantification of the isolated subsets of HCC EVs. One of the major challenges emerging in the field of EV utilization for clinical use is the lack of robust and reproducible methods for the isolation of subpopulations of tumor-associated EVs. Conventional methods for isolating EVs, such as ultracentrifugation, filtration, and precipitation, are incapable of isolating subpopulation of tumor-associated EVs from total EVs. New research efforts have been devoted to exploring immunoaffinity-based capture techniques for enriching tumor- associated EVs from the plasma samples of patients with different solid tumors. However, there are challenges identified for the single antibody-mediated tumor-derived EV enriching approaches, such as limited sensitivity/specificity and a need for multiple capture antibodies to overcome the tumor heterogeneity. In order to address these concerns, our research team developed HCC EV SPA, which combines a click chemistry- mediated tumor-associated EV isolation, and downstream 4-plex real-time immuno-PCR. HCC EV SPA is capable of highly sensitive and specific quantification of 32 subpopulations of HCC EVs in patients’ plasma samples, based on the combined use of 8 different HCC-associated surface protein markers and four EV surface markers. The long-term goal of this R01 proposal is to develop, refine, and validate the HCC EV SPA for detecting early-stage HCC from at-risk liver cirrhotic patients by quantifying subpopulations of HCC EVs.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $661,505 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	3	6/16/2025	NON-COMPETING CONTINUATION	$661,505
														Subtotal = $661,505

Issue Date FY: 2024 ( Subtotal = $628,431 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	2	6/19/2024	NON-COMPETING CONTINUATION	$628,431
														Subtotal = $628,431

Issue Date FY: 2023 ( Subtotal = $674,097 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	1	6/14/2023	NEW	$674,097
														Subtotal = $674,097

Grand Total All Awards = $1,964,033

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Click Chemistry-Mediated Surface Protein Assay for Quantifying Subpopulations of Hepatocellular Carcinoma-associated Extracellular Vesicles

Award Number: R01CA277530

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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