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WT1 as an oncogene and therapeutic target in anaplastic Wilms tumor

Award Number: K08CA255569
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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WT1 as an oncogene and therapeutic target in anaplastic Wilms tumor - PROJECT SUMMARY/ABSTRACT Wilms tumor is the most common kidney cancer in children. High-risk patient groups continue to have dismal outcomes. The greatest predictor of a poor outcome is microscopic detection of diffuse anaplasia (unfavorable histology). This finding accounts for 50% of deaths from this disease and is associated with treatment resistance. Diffuse anaplasia (unfavorable histology) is caused by mutation in the TP53 gene that occurs late in a tumor with previously favorable histology. While TP53 mutation is associated with treatment resistance and poor outcomes, it could also result in new tumor vulnerabilities. The long-term goal of our research is to identify and exploit new therapeutic vulnerabilities in anaplastic Wilms tumor using targeted approaches. Wilms tumors with WT1 mutation do not go on to develop TP53 mutation and do not develop anaplasia. Previous evidence shows that the gene WT1 serves as a tumor suppressor in Wilms tumor. However, our central hypothesis is that WT1 functions as an oncogene in anaplastic Wilms tumor. Tumors with WT1 mutation do not develop anaplasia and WT1 and TP53 mutations do not occur in the same pediatric cancer patient tumors of any histology. Therefore, we hypothesize that WT1 mutations and TP53 mutations in the same Wilms tumor cell could be lethal events to the cancer cell. Aim 1 will test the hypothesis that loss of function WT1 and TP53 mutations are synthetic lethal events in Wilms tumor cancer cells. To test this hypothesis, we will model knockout of WT1 in TP53-mutant anaplastic Wilms tumor cells in vitro. We will also introduce a TP53 mutation into a mouse Wilms tumor model that has loss of WT1 function. Our preliminary data show that WT1 is necessary for activation of the telomerase pathway in Wilms tumor. Telomerase (critical portion coded by TERT gene) adds DNA repeats to the ends of chromosomes to counteract chromosomal shortening caused by rapidly dividing cancer cells. Aim 2 will test the hypothesis that functional WT1 is necessary for increased TERT expression and telomerase activity in anaplastic Wilms tumor. By knocking out WT1 in vitro and in a mouse model system, we aim to determine if WT1 is necessary for gain of telomerase function. We also will test the telomere targeted therapy 6-Thio-dG in mouse xenograft models using human patient tumor samples. We have identified that the histone demethylase KDM6B (an enzyme that modifies how DNA is bound to histones) regulates WT1 levels in Wilms tumor cells. We have shown that inhibition of KDM6B lowers WT1 levels. Aim 3 will test the hypothesis that KDM6B upregulates WT1 in Wilms tumor and can therefore be exploited as a therapeutic target. We plan to perform in vitro experiments which impair KDM6B function on the chemical and genetic levels in order to determine its effect on WT1 and anaplastic Wilms tumor cell behavior. We also aim to test the KDM6B inhibitor GSK-J4 in mouse xenograft models using human patient tumor samples. The expected outcome of these studies will be a greatly improved understanding of how WT1 functions in anaplastic Wilms tumor and the evaluation of WT1, telomerase, and KDM6B as preclinical therapeutic targets in anaplastic Wilms tumor.


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 = $194,741 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	5	12/12/2024	NON-COMPETING CONTINUATION	$194,741
														Subtotal = $194,741

Issue Date FY: 2024 ( Subtotal = $194,741 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	4	12/21/2023	NON-COMPETING CONTINUATION	$194,741
														Subtotal = $194,741

Issue Date FY: 2023 ( Subtotal = $265,113 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	3	12/13/2022	NON-COMPETING CONTINUATION	$265,113
														Subtotal = $265,113

Issue Date FY: 2022 ( Subtotal = $265,113 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	2	1/19/2022	NON-COMPETING CONTINUATION	$265,113
														Subtotal = $265,113

Issue Date FY: 2021 ( Subtotal = $265,113 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	1	12/18/2020	NEW	$265,113
														Subtotal = $265,113

Grand Total All Awards = $1,184,821

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WT1 as an oncogene and therapeutic target in anaplastic Wilms tumor

Award Number: K08CA255569

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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