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Targeted proteomics of MUC16 to enable early detection of ovarian cancer recurrence

Award Number: R21CA267532
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Targeted proteomics of MUC16 to enable early detection of ovarian cancer recurrence - High-grade serous ovarian cancer (HGSOC) is a deadly disease, in large part because most cases recur, and little can be done after that point. New diagnostic tools are urgently needed to improve HGSOC management and detect recurrence before clinical presentation. MUC16 is overexpressed on ovarian cancer cells and bears the CA125 epitope that is currently detected in clinical assays. The value of CA125 titers for surveillance is an active area of debate within the gynecologic oncology community. Some studies report no survival benefit, while others point to higher quality secondary cytoreductive surgery if action is taken quickly. Successfully fighting HGSOC requires that new assays are developed for more reliable and sensitive detection of recurrent disease. Our goal is to develop a new biomarker for HGSOC recurrence by fundamentally rethinking MUC16. Instead of considering MUC16 as the carrier of the CA125 epitope, we recognize that MUC16 itself is present as multiple diverse proteoforms. Because of variation in mRNA splicing, post-translational cleavage, and post- translational modifications, the population of MUC16 molecules present in an individual is heterogeneous. MUC16 is abundantly glycosylated, and glycan profiles of MUC16 derived from cancer cells is an untapped wealth of diagnostic information that is now lost using the existing peptide-based CA125 immunoassay. The goal of this project is to develop a method to enrich MUC16 from the serum of women undergoing treatment for HGSOC and analyze MUC16 using targeted (glyco)proteomics. We hypothesize that the molecular diversity of MUC16 revealed using modern bioanalytical and computational tools will enable novel diagnostics to detect HGSOC resurgence earlier than is currently possible. This hypothesis will be investigated by pursuing three research aims. In Aim 1 (Develop methods to quantitate MUC16 (glyco)peptide libraries using mass spectrometry), MUC16 from banked peritoneal fluid of HGSOC patients will be used to develop an optimized novel targeted mass spectrometry method for identification of MUC16 glycopeptides and peptides before and after deglycosylation. A parallel reaction monitoring (PRM) inclusion list will be generated by examination of in silico digest data and experimental MS/MS data. In Aim 2 (Develop a microscale separation method to enrich MUC16 from serum), we will adapt an immunoaffinity-free protocol that we developed to enrich MUC16 from peritoneal fluid to isolate the mucin from serum samples. A cartridge-based format will be used to capture MUC16 based on its negative charge and specific glycosylation. Finally, in Aim 3: (Develop pilot data on longitudinal variations in MUC16 (glyco)peptide libraries in patients with HGSOC before and during treatment), longitudinal serum samples from HGSOC patients will be enriched for MUC16 using the microscale protocol. Samples will be proteolyzed and analyzed by nLC-PRM. Quantitative (glyco)peptide maps for MUC16 from each patient will be compared longitudinally. The (glyco)peptides that deviate most between samples will be determined as potential diagnostic markers for early detection of recurring HGSOC in a future study.


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: 2026 ( Subtotal = -$32,884 )
2026	2023	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Cancer Treatment Research	000	3	12/4/2025	NON-COMPETING CONTINUATION	-$32,884
														Subtotal = -$32,884

Issue Date FY: 2023 ( Subtotal = $167,270 )
2023	2023	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Cancer Treatment Research	000	3	6/30/2023	NON-COMPETING CONTINUATION	$167,270
														Subtotal = $167,270

Issue Date FY: 2022 ( Subtotal = $244,713 )
2022	2022	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Cancer Treatment Research	004	2	9/6/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$25,644
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Treatment Research	000	1	12/22/2021	NEW	$244,713
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Treatment Research	001	1	7/21/2022	NEW	-$219,069
2022	2022	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Cancer Treatment Research	002	2	7/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$219,069
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Treatment Research	003	1	9/6/2022	NEW	-$25,644
														Subtotal = $244,713

Grand Total All Awards = $379,099

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Targeted proteomics of MUC16 to enable early detection of ovarian cancer recurrence

Award Number: R21CA267532

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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