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Overcoming Leukemia Chemoresistance in the Central Nervous System

Award Number: R37CA240846
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/04/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Overcoming Leukemia Chemoresistance in the Central Nervous System - ABSTRACT Central nervous system (CNS) relapse is a major cause of treatment failure among patients with acute lymphoblastic leukemia (ALL). Notably, isolated CNS relapse occurs in ~3-8% of children with ALL and accounts for 30–40% of initial relapses in some clinical trials. Furthermore, current CNS-directed therapies are associated with significant toxicities. As a result, novel CNS-directed leukemia therapies are urgently needed to improve long-term outcomes while decreasing treatment-related morbidity. Although extensive research has demonstrated a critical role of the bone marrow microenvironment in leukemia biology, the impact of the CNS microenvironment on leukemia cell survival and chemoresistance is largely unknown. We developed a novel ex vivo co-culture system and an in vivo xenotransplantation approach to investigate the effects of the CNS niche on leukemia biology and chemoresistance. We then used these model systems to identify that 1) leukemia cells cultured in cerebral spinal fluid (CSF) in vitro and in vivo have diminished survival relative to serum or media, 2) leukemia cells predominantly localize to the meninges within the CNS, and 3) leukemia cells co-cultured with meningeal cells, or associated with the meninges of mice, exhibit enhanced survival and chemoresistance. We then identified that direct meningeal-leukemia interactions promote leukemia cell survival by modulating apoptosis balance, cell cycle progression, and quiescence. Importantly, leukemia chemoresistance was reversible and overcome by detaching the leukemia cells from the meninges. We then used a co-culture adhesion assay to identify drugs that disrupt the interaction between leukemia and meningeal cells. In addition to identifying several drugs that inhibit canonical cell adhesion targets and pathways, including the CXCR4 antagonist AMD3100, we found that Me6TREN, a novel small-molecule hematopoietic stem cell (HSC) mobilizing compound, also disrupts the interaction between leukemia and meningeal cells. This work demonstrates that the meninges exert a unique and critical influence on leukemia chemoresistance and defines novel mechanisms of CNS relapse beyond the well-described role of the blood- brain barrier. Based on this work, our central hypothesis is that the leukemia-meningeal cell interaction is a critical regulator of leukemia cell survival and chemoresistance in the CNS. Moreover, from a therapeutic standpoint, we hypothesize that niche disruption may be more efficacious in the CNS than in the bone marrow because of the less supportive environment of the CSF relative to the blood or serum. The objectives in this proposal are to use our in vitro and in vivo model systems for CNS leukemia to dissect the molecular mechanisms that mediate leukemia adhesion (Aim 1) and chemoresistance (Aim 2) in the CNS and test novel, clinically translatable therapies for CNS leukemia including Me6TREN and AMD3100 (Aim 3).


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 = $317,049 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Biology Research	002	6	6/11/2025	EXTENSION WITH OR WITHOUT FUNDS	$19,325
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Biology Research	000	6	4/7/2025	EXTENSION WITH OR WITHOUT FUNDS	$317,049
2025	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Biology Research	001	5	6/11/2025	NON-COMPETING CONTINUATION	-$19,325
														Subtotal = $317,049

Issue Date FY: 2024 ( Subtotal = $334,662 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	001	5	4/22/2024	NON-COMPETING CONTINUATION	$17,614
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	5	2/19/2024	NON-COMPETING CONTINUATION	$317,048
														Subtotal = $334,662

Issue Date FY: 2023 ( Subtotal = $345,230 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	4	3/10/2023	NON-COMPETING CONTINUATION	$345,230
														Subtotal = $345,230

Issue Date FY: 2022 ( Subtotal = $352,275 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	001	3	5/20/2022	NON-COMPETING CONTINUATION	$35,227
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	3	3/14/2022	NON-COMPETING CONTINUATION	$317,048
														Subtotal = $352,275

Issue Date FY: 2021 ( Subtotal = $352,275 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	2	2/22/2021	NON-COMPETING CONTINUATION	$352,275
														Subtotal = $352,275

Issue Date FY: 2020 ( Subtotal = $352,275 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	1	3/3/2020	NEW	$352,275
														Subtotal = $352,275

Grand Total All Awards = $2,053,766

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Overcoming Leukemia Chemoresistance in the Central Nervous System

Award Number: R37CA240846

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/04/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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