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Novel targeted therapy to reduce health disparities in pediatric leukemia

Award Number: R01CA278226
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Novel targeted therapy to reduce health disparities in pediatric leukemia - ABSTRACT Hispanic/Latino (H/L) children and adolescents have a 40% higher death rate than non-Hispanic whites (NHW) after correcting socioeconomic factors. Recently, we identified a highly increased incidence of deletion of one IKZF1 allele in H/L children, which provided a biological rationale for the worse prognosis of B-cell acute lymphoblastic leukemia (B-ALL) in this population. The very high incidence (29%) makes the deletion of one IKZF1 allele the most frequent genetic alteration that confers adverse prognosis in B-ALL in H/L children. Thus, understanding the biological basis for resistance to chemotherapy and developing novel therapies to treat B-ALL with deletion of one IKZF1 allele will reduce the health disparity in survival for Hispanic/Latino children with ALL. The IKZF1 gene encodes a DNA-binding protein, IKAROS, which functions as a transcriptional regulator. Our published data showed that, in B-ALL, IKAROS phosphorylation by the oncogenic Casein Kinase II (CK2) reduces IKAROS DNA-binding affinity and abolishes its function as a transcriptional regulator. Our new preliminary data suggest that CK2 impairs the ability of IKAROS to repress transcription of two key genes involved in the thiopurine pathway, resistance to 6-mercaptopurine (6-MP) treatment, and relapse: TPMT and NT5C2. Treatment with CK2-specific inhibitor, CX-4945, restores IKAROS-mediated repression of the TPMT and NT5C2 genes in primary B-ALL cells from H/L children. In vitro treatment of B-ALL with CX-4945 in combination with 6-MP exhibits a strong synergistic cytotoxic effect. Our overall hypothesis is that overexpression of CK2 in high-risk B-ALL of H/L children impairs IKAROS’ ability to transcriptionally repress the genes that regulate resistance to treatment with 6-MP, and that CK2 inhibition will restore IKAROS function as a transcriptional repressor of these genes, resulting in increased sensitivity to 6-MP. This hypothesis will be tested in vivo, using various biological models. We will define the mechanism through which IKAROS regulates the thiopurine pathway in primary B-ALL cells from H/L children. The effect of increased CK2 expression on thiopurine pathway and IKAROS function will be analyzed in patient-derived xenografts (PDXs), generated from B-ALL from H/L children. Finally, we will establish the therapeutic efficacy of combination treatment with CK2 inhibitor (CX-4945) and 6-mercaptopurine (6-MP) in a preclinical model of B-ALL from H/L children. Results of the project will provide a novel insight into the regulation of the thiopurine pathway and help develop novel treatments for high-risk B-ALL in H/L children and reduce childhood cancer health disparities.


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 = $541,022 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Treatment Research	000	3	4/23/2025	NON-COMPETING CONTINUATION	$486,921
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Treatment Research	001	3	9/24/2025	NON-COMPETING CONTINUATION	$54,101
														Subtotal = $541,022

Issue Date FY: 2024 ( Subtotal = $513,972 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Treatment Research	000	2	4/29/2024	NON-COMPETING CONTINUATION	$513,972
														Subtotal = $513,972

Issue Date FY: 2023 ( Subtotal = $541,022 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Treatment Research	000	1	5/26/2023	NEW	$541,022
														Subtotal = $541,022

Grand Total All Awards = $1,596,016

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Novel targeted therapy to reduce health disparities in pediatric leukemia

Award Number: R01CA278226

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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