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Development of a Mouse Model to Study Targeted Therapy to Prevent CNS Invasion by Pediatric T-ALL

Award Number: R03CA270815
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Development of a Mouse Model to Study Targeted Therapy to Prevent CNS Invasion by Pediatric T-ALL - TITLE: Development of a Mouse model to test targeted therapy to prevent CNS Invasion by Pediatric T- ALL Abstract Leukemia is the most frequent pediatric cancer with acute lymphoblastic leukemia (ALL) being the most common leukemia type in children. In 15-20% of pediatric T-cell ALL (T-ALL) patients, the cancer invades the Central Nervous System (CNS), a site which is protected from systemic chemotherapies by the blood brain barrier. The invading leukemic cells are reservoirs, which can emerge and re-enter the circulation following treatment and cause T-ALL relapse. To prevent relapse, pediatric patients are treated with cranial irradiation and toxic chemotherapies, which are injected directly into the CNS. It is not surprising that these treatments can lead to morbid life-long side effects such as reduced intelligence, stunted growth, and secondary cancers in the CNS. Generally, the T-ALL has entered the CNS prior to diagnosis, and it is unclear if blocking the entry of T-ALL into the CNS at that point, after they have already entered, provides any therapeutic benefit. The overarching three goals of this proposal are: 1) to develop a mouse model of T- ALL that recapitulates human T-ALL, in which we can see the cells in living animals 2) to determine if blocking T-ALL cells from entering the CNS, prevents further T-ALL CNS invasion and 3) to determine if the T-ALL that has invaded the CNS will eventually clear the CNS and return to the circulation. Our long-term goal is to reduce or eliminate the need for damaging intrathecal or cranial treatments in patients with T-ALL. Our studies are based on a human xenograft mouse model of T-ALL, which revealed that during leukemogenesis, expression of NOTCH1, a transcription factor which is expressed in more than 80% of pediatric T-ALLs, induces expression of CC chemokine receptor 7 (CCR7). The study revealed that activation of CCR7 in T-ALL by one of its ligands, CCL19 promotes chemotactic migration of T-ALL into the CNS. Our proposal is based on a mouse model obtained from Dr. Monica Justice which uses an inducible CCR7(+)ROSA26 floxed-stop-PRDM14 (R26PR) locus. When crossed to an MX1-Cre these R26PR mice develop leukemia in response to overexpression of NOTCH1, which invades the CNS. Subsequent breeding of these mice with ROSA26 floxed-stop luciferase mice will result in Cre-recombinase induced expression of bioluminescent luciferase in T-ALL cells. To confirm a role for CCR7 in the invasion of the CNS, these R26PR mice will be crossed with our own CCR7 conditional knockout mice (CCR7floxed/floxed (CCR7f/f)) to produce R26PRDM14/CCR7f/f/MX1-CRE mice. Generation of this mouse is aim 1. Determining which immune cells co-localize with T-ALL cells upon entry into the CNS is aim2 and determining if blocking CCR7 using the CCL19 antagonist, CCL198-83 prevents or significantly reduces T-ALL CNS invasion, clears the CNS of T-ALL and increases mouse survival is aim 3. Ultimately, if successful, this mouse model will provide a tool for developing novel peptide therapies that can block T-ALL CNS invasion, without causing long-term CNS damage in patients and to study mechanisms of CNS invasion.


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 = -$964 )
2026	2024	THE UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Cancer Biology Research	000	2	2/10/2026	NON-COMPETING CONTINUATION	-$964
														Subtotal = -$964

Issue Date FY: 2024 ( Subtotal = $76,750 )
2024	2024	UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Cancer Biology Research	000	2	11/2/2023	NON-COMPETING CONTINUATION	$76,750
														Subtotal = $76,750

Issue Date FY: 2023 ( Subtotal = $76,750 )
2023	2023	UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Cancer Biology Research	000	1	12/15/2022	NEW	$76,750
														Subtotal = $76,750

Grand Total All Awards = $152,536

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Development of a Mouse Model to Study Targeted Therapy to Prevent CNS Invasion by Pediatric T-ALL

Award Number: R03CA270815

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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