Tuesday, July 1, 2025 7/1/2025

Understanding mechanisms of BTK inhibitor and degrader resistance in patients with chronic lymphocytic leukemia

Award Number: R01CA292653
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Understanding mechanisms of BTK inhibitor and degrader resistance in patients with chronic lymphocytic leukemia - Project Summary Covalent inhibitors of Bruton’s tyrosine kinase (BTK) are effective in multiple B-cell malignancies but patients discontinue these agents due to resistance and intolerance. Highly selective and reversible non-covalent BTK inhibitors have been developed to overcome these problems and are currently being tested in clinical trials in patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Despite these beneficial features of non-covalent BTK inhibitors and a high overall response rate seen in early clinical trials, some patients did not respond to treatment or relapsed after initial response to monotherapy. This project’s broad and long-term goals are to better understand these resistance mechanisms leading to relapse and design better combination strategies or use of novel drugs to overcome this resistance. Our specific aims are to elucidate the molecular mechanisms of resistance to this novel class of BTK inhibitors by interrogating the signaling pathways in mutant BTK cells that are kinase deficient. We plan to comprehensively evaluate the dependence of kinase dead BTK mutations on potential surrogate kinases activated by mutant BTK. We are also testing the requirement for BTK for survival and signaling in cells with PLCG2 mutations. Lastly, we will identify the genomic basis for BTK degrader resistance. Given the widespread use of BTK inhibitors across CLL and B-cell malignancies, and the increasing incidence of patients with acquired resistance to non-covalent BTK inhibitors, the results of this study will have major therapeutic importance for patients with a variety of B- cell malignancies. Our findings will inform future application of disease monitoring on non-covalent BTK inhibitors and about the development of resistance mechanisms with BTK degraders that are now being used in clinical trials.


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 = $351,131 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Treatment Research	000	2	6/13/2025	NON-COMPETING CONTINUATION	$351,131
														Subtotal = $351,131

Issue Date FY: 2024 ( Subtotal = $351,131 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Treatment Research	000	1	7/1/2024	NEW	$351,131
														Subtotal = $351,131

Grand Total All Awards = $702,262

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Understanding mechanisms of BTK inhibitor and degrader resistance in patients with chronic lymphocytic leukemia

Award Number: R01CA292653

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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