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Defining and targeting asparaginase resistance mechanisms in high-risk acute leukemias

Award Number: R01CA193651
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Defining and targeting asparaginase resistance mechanisms in high-risk acute leukemias - ABSTRACT Asparaginase, an antileukemic enzyme that depletes the nonessential amino acid asparagine, is a core component of front-line therapy for acute lymphoblastic leukemias. However, the development of resistance to asparaginase-based therapy is a common problem with a poor prognosis, and the biology underlying asparaginase response and resistance is not well understood. Using a genome-wide genetic screen, we recently found that Wnt pathway activation profoundly sensitizes drug-resistant leukemias to asparaginase. This effect occurs in distinct treatment-resistant subtypes of acute leukemia, including T-ALL, hypodiploid B-ALL, and acute myeloid leukemia, but not in normal hematopoietic progenitors. Asparaginase sensitization is independent of the canonical β-catenin branch of Wnt signaling. Instead, this effect is mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), an understudied branch of Wnt signaling that inhibits GSK3-dependent protein ubiquitination and proteasomal degradation. Inhibiting the alpha isoform of GSK3 is sufficient to phenocopy this effect. In vivo, the combination of GSK3α-selective inhibition and asparaginase has profound therapeutic activity against patient-derived xenografts that are completely resistant to monotherapy with either agent. Thus, asparaginase-resistant leukemias survive treatment with this enzyme by relying on protein degradation, a catabolic source of amino acids, to replenish the pool of intracellular asparagine. This adaptive response is blocked by Wnt pathway activation, or by selective inhibition of GSK3α. However, the molecular determinants of response and resistance to the combination of GSK3α inhibition and asparaginase are unknown. These knowledge gaps are major obstacles to the rational application of this potent therapeutic combination for maximal clinical benefit, which will be addressed by investigating the following Specific Aims: 1) Define the molecular basis for the therapeutic index of GSK3α inhibition and asparaginase, and 2) Investigate why asparaginase resistance is solely dependent on GSK3α, when its closely related paralog GSK3β is redundant for regulation of canonical Wnt/β-catenin signaling. Successful completion of this proposal is expected to reveal major insights into the cellular response to amino acid starvation and its interaction with Wnt signaling. These processes are fundamental to metazoan biology, yet their molecular regulation and therapeutic exploitation remain poorly understood. We are uniquely poised to translate these advances into highly innovative and effective therapeutic strategies to maximize the therapeutic index of asparaginase in cancer therapy.


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 = $0 )
2026	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	000	11	11/18/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	002	10	1/31/2025	NON-COMPETING CONTINUATION	$0
2025	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	10	10/22/2024	NON-COMPETING CONTINUATION	-$373,507
2025	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	001	11	10/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$373,507
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $420,464 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	10	5/29/2024	NON-COMPETING CONTINUATION	$420,464
														Subtotal = $420,464

Issue Date FY: 2023 ( Subtotal = $433,739 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	9	5/31/2023	NON-COMPETING CONTINUATION	$433,739
														Subtotal = $433,739

Issue Date FY: 2022 ( Subtotal = $433,736 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	8	6/10/2022	NON-COMPETING CONTINUATION	$433,736
														Subtotal = $433,736

Issue Date FY: 2021 ( Subtotal = $450,484 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	7	6/1/2021	NON-COMPETING CONTINUATION	$450,484
2021	2019	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	5	3/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $450,484

Issue Date FY: 2020 ( Subtotal = $453,934 )
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	6	5/27/2020	COMPETING CONTINUATION	$453,934
														Subtotal = $453,934

Issue Date FY: 2019 ( Subtotal = $429,996 )
2019	2019	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	5	9/4/2019	NON-COMPETING CONTINUATION	$429,996
														Subtotal = $429,996

Issue Date FY: 2018 ( Subtotal = $443,296 )
2018	2018	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	4	8/14/2018	NON-COMPETING CONTINUATION	$443,296
														Subtotal = $443,296

Issue Date FY: 2017 ( Subtotal = $446,954 )
2017	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	3	8/16/2017	NON-COMPETING CONTINUATION	$446,954
														Subtotal = $446,954

Issue Date FY: 2016 ( Subtotal = $451,095 )
2016	2016	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	8/1/2016	NON-COMPETING CONTINUATION	$451,095
														Subtotal = $451,095

Issue Date FY: 2015 ( Subtotal = $450,867 )
2015	2015	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	7/27/2015	NEW	$450,867
														Subtotal = $450,867

Grand Total All Awards = $4,414,565

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Defining and targeting asparaginase resistance mechanisms in high-risk acute leukemias

Award Number: R01CA193651

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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