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Strategies to target BCR-ABL1 compound mutants in https://apps.era.nih.gov/facts/fcdataGrants/viewFCData.era?applId=11005218#app-addressesCML and Ph+ ALL

Award Number: R01CA257602
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/10/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Strategies to target BCR-ABL1 compound mutants in https://apps.era.nih.gov/facts/fcdataGrants/viewFCData.era?applId=11005218#app-addressesCML and Ph+ ALL - Abstract: Philadelphia chromosome-positive (Ph+) leukemia is caused by BCR-ABL1, a constitutively active fusion kinase. Tyrosine kinase inhibitors (TKIs) targeting the ATP site of BCR-ABL1 are effective in treating chronic-phase chronic myeloid leukemia (CP-CML) yet minimally effective at treating blast-phase CML and Ph+ acute lymphoblastic leukemia. In the 20 years since the approval of the first TKI in all of medicine, imatinib, TKIs have dramatically improved survival of patients with CP-CML, resulting in a projected increase of CML prevalence from 70,000 Americans in 2010 to 180,000 in 2050. Despite this progress, TKI-resistant CML remains a challenge, with >1,000 deaths annually in the U.S. At least 50% of TKI treatment failure arises through mutations in BCR-ABL1. Laboratory studies on the five FDA-approved BCR-ABL1 TKIs have established their mutational profiles against the >30 mutations observed in patients. In aggregate, these TKIs cover the clinical spectrum of BCR-ABL1 single point mutants. Ponatinib is the only TKI that is clinically effective against the T315I gatekeeper mutant. However, BCR-ABL1 compound mutants, defined as 2 mutations in the same BCR-ABL1 allele, that include T315I with any second mutation are resistant to all approved TKIs, including ponatinib, leaving these patients with no further treatment options. Asciminib is the first inhibitor in clinical development that binds the BCR-ABL1 myristoyl site, an allosteric site distant from the ATP site, to enforce an autoinhibited, inactive conformation. We established that asciminib, like ponatinib, is not effective against T315I-inclusive compound mutants, yet combining ponatinib (but not nilotinib or dasatinib) with asciminib is extremely effective at inhibiting many T315I-inclusive compound mutant forms of BCR-ABL1. This discovery provides the basis for a novel therapeutic strategy to address an entirely unmet medical need and is the foundation of this proposal. In Aim 1, we will use computational, biophysical and crystallographic methods to decipher how ponatinib re-sensitizes compound mutant BCR-ABL1 to asciminib. We will test the combination in relevant mouse models and in primary leukemia samples. In Aim 2A, we will develop a therapeutic strategy for clinically resistant BCR-ABL1 compound mutants that are not inhibited by the combination of ponatinib with asciminib. Instead, we will target these mutants for proteasomal degradation using an asciminib proteolysis targeting chimera (PROTAC) strategy. Unlike TKIs, PROTACs are effective even upon transient or weak binding. We will test the hypothesis that ponatinib-induced stabilization of the myristoyl site is the initiating event that allows subsequent binding of an asciminib-PROTAC and proteasomal degradation of compound mutant BCR-ABL1. In Aim 2B, we will develop a ponatinib-PROTAC strategy for compound mutants carrying a myristoyl site resistance mutation. Our work will provide a rationale for clinical evaluation of ponatinib combined with asciminib as a therapy for currently untreatable BCR-ABL1 compound mutant leukemia. Compound mutations are also a major cause of resistance in acute myeloid leukemia, melanoma, and lung cancer, and our study will provide a blueprint for treating these malignancies.


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 = $377,438 )
2025	2025	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Treatment Research	001	5	7/4/2025	NON-COMPETING CONTINUATION	$37,744
2025	2025	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Treatment Research	000	5	12/6/2024	NON-COMPETING CONTINUATION	$339,694
														Subtotal = $377,438

Issue Date FY: 2024 ( Subtotal = $358,566 )
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$18,872
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Treatment Research	000	4	12/29/2023	NON-COMPETING CONTINUATION	$339,694
														Subtotal = $358,566

Issue Date FY: 2023 ( Subtotal = $369,889 )
2023	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Treatment Research	000	3	1/6/2023	NON-COMPETING CONTINUATION	$339,694
2023	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Treatment Research	001	3	9/14/2023	NON-COMPETING CONTINUATION	$30,195
														Subtotal = $369,889

Issue Date FY: 2022 ( Subtotal = $369,889 )
2022	2022	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Treatment Research	004	2	7/7/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$30,195
2022	2022	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Treatment Research	001	2	3/18/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$339,694
2022	2022	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Treatment Research	003	2	4/18/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$202,665
2022	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Treatment Research	000	1	3/18/2022	NEW	$0
2022	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Treatment Research	002	1	4/18/2022	NEW	-$202,665
														Subtotal = $369,889

Issue Date FY: 2021 ( Subtotal = $348,844 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Treatment Research	000	1	11/27/2020	NEW	$348,844
														Subtotal = $348,844

Grand Total All Awards = $1,824,626

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Strategies to target BCR-ABL1 compound mutants in https://apps.era.nih.gov/facts/fcdataGrants/viewFCData.era?applId=11005218#app-addressesCML and Ph+ ALL

Award Number: R01CA257602

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/10/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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