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The Role of Klotho Beta in Colorectal Cancer Tumorigenesis

Award Number: F30CA257492
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/04/2021
PERIOD OF PERFORMANCE END DATE: 01/03/2024

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The Role of Klotho Beta in Colorectal Cancer Tumorigenesis - Abstract Colorectal cancer (CRC) is both the third most common and deadliest cancer in the United States. Despite recent advances in treatment, the 5-year survival rate remains poor due to multiple factors including delayed diagnosis, chemoresistance, and disease heterogeneity. Altered expression of enteroendocrine protein signaling components consisting of Fibroblast Growth Factor Receptor 4 (FGFR4), its ligand Fibroblast Growth Factor 19 (FGF19), and co-receptor Klotho Beta (KLB) recently have been implicated in various cancers. Specific to CRC, the role of KLB remains elusive, although FGF19 and FGFR4 have more established oncogenic functions. An objective of this proposed research is to delineate KLB’s function in CRC. The work is predicated on the analysis of CRC RNA-seq data from The Cancer Genome Atlas (TCGA) database consistently showing significant repression in CRC generally and across all subtypes. Collectively, it is necessary to further investigate and validate KLB’s role in CRC, focusing on how KLB modulates oncogenic FGFR4-FGF19 signaling in the larger context of epithelial-mesenchymal transition (EMT) and tumorigenesis. Thus, our overall hypothesis is that KLB demonstrates tumor suppressor properties in CRC by negatively regulating oncogenic, EMT-promoting FGFR4-FGF19 signaling. Specific Aim 1 will test the hypothesis by analyzing detailed clinical parameters via informatics to assess the prognostic value of KLB deficiency in CRC and reveal its impact on tumor dynamics in vitro and in vivo. Our preliminary data reveals tumor-suppressor-like properties of KLB as its expression is directly associated with treatment success, microsatellite stability, survivability and inversely with pathologic stage. Additionally, KLB downregulation occurs as early as the adenoma stage further supported by a CRC cell line panel showing global KLB repression which directly correlated with differentiation status. Finally, KLB expression was enhanced in two separate in vitro CRC models of differentiation and its transgenic overexpression was associated with increased cellular organization and polarization of HT29 cells compared to CrisprCas9-induced knock down. Specific Aim 2 will investigate KLB’s mechanism of action by testing FGFR4-FGF19 signaling as the major effector pathway through which KLB affects CRC. In support of this Aim, we present compelling new preliminary evidence showing that KLB expression positively correlates with Farnesoid-X-Receptor (FXR), a known tumor suppressor and target of FGFR4 signaling, within the clinical data thereby indicating possible crosstalk. Additionally, chemical agonism of FXR induces KLB expression in Caco2 cells in vitro. By performing these studies, we expect to (i) Establish KLB’s clinical implications in CRC, and (ii) Demonstrate that KLB affects CRC mechanistically through regulation of FGFR4-FGF19 signaling. Overall, this study will establish a tentative role for KLB in CRC and how its presence impacts oncogenic FGFR4-FGF19 signaling. The ultimate goal of this proposal is to utilize KLB expression to predict prognosis, treatment response and serve as a potential therapeutic target for improving CRC patient outcomes.


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 = -$9,791 )
2025	2023	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Cancer Research Manpower	000	3	11/27/2024	NON-COMPETING CONTINUATION	-$9,791
														Subtotal = -$9,791

Issue Date FY: 2023 ( Subtotal = $33,250 )
2023	2023	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Cancer Research Manpower	001	3	6/6/2023	NON-COMPETING CONTINUATION	$942
2023	2023	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Cancer Research Manpower	000	3	12/27/2022	NON-COMPETING CONTINUATION	$32,308
														Subtotal = $33,250

Issue Date FY: 2022 ( Subtotal = $32,308 )
2022	2022	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Cancer Research Manpower	000	2	12/3/2021	NON-COMPETING CONTINUATION	$31,592
2022	2022	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Cancer Research Manpower	001	2	5/30/2022	NON-COMPETING CONTINUATION	$716
														Subtotal = $32,308

Issue Date FY: 2021 ( Subtotal = $31,592 )
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Cancer Research Manpower	000	1	12/15/2020	NEW	$31,076
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Cancer Research Manpower	002	1	2/3/2021	NEW	$0
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Cancer Research Manpower	001	1	2/3/2021	NEW	$516
														Subtotal = $31,592

Grand Total All Awards = $87,359

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The Role of Klotho Beta in Colorectal Cancer Tumorigenesis

Award Number: F30CA257492

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/04/2021

PERIOD OF PERFORMANCE END DATE: 01/03/2024

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