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The HDAC3 pathway in LKB1-mutant lung cancer and senescence

Award Number: K22CA251636
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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The HDAC3 pathway in LKB1-mutant lung cancer and senescence - Project Summary/Abstract The STK11/LKB1 tumor suppressor is mutated in ~15% of Non-Small Cell Lung Cancer (NSCLC) cases, making it the third most frequent genetic alteration. LKB1 is frequently co-mutated with Kras, and LKB1-mutant tumor biology is becoming increasingly of interest to the cancer field as the uniqueness of the underlying tumor biology coupled with the lack of targeted therapy options is gaining attention. Recent work identified a potent tumor promoting function of the HDAC3 complex in Kras-driven NSCLC, and revealed that HDAC3 cooperates with the lung cancer lineage transcription factor NKX2-1 to drive a unique transcriptional program in lung cancer cells with LKB1 mutation. Interestingly, regardless of LKB1 mutational status, HDAC3 was also found to directly repress the Senescence-Associated Secretory Phenotype (SASP) via p65 NF-kB. The work outlined in this proposal aims to (1) elucidate the mechanistic explanations for the observed transcriptional vulnerabilities unique to LKB1 mutant tumors, and to (2) define how the HDAC3 protein complex regulates the SASP and immune cell recruitment to impact lung tumor growth control. Experiments will determine HDAC3 and NKX2-1 genomic binding patterns and interacting partners specific to LKB1-mutant cells, whether Class IIa HDACs contribute to the LKB1 specificity of HDAC3 function, and therapeutic response to HDAC3 inhibition in LKB1-mutant tumors. These studies will also define how HDAC3 impacts p65 genome binding and activity, identify which Nuclear Receptors are required for HDAC3 repression of the SASP, and profile the HDAC3-dependent intratumoral immune infiltrate and its contribution to growth control in vivo. Insights gained from this work will contribute to the understanding of key LKB1-specific transcriptional pathways and how they may be impinged upon therapeutically. This research also aims to define the mechanism mediating HDAC3 control of the SASP, which will facilitate exploration of key questions about SASP involvement in tumor growth control more broadly. The candidate holds a Ph.D. in Biochemistry and is currently completing her post-doctoral training with Dr. Reuben Shaw at the Salk Institute for Biological Studies. The candidate’s career goal is to obtain a tenure-track faculty position studying transcriptional deregulation in cancer. These studies will provide the foundation for a continued research program in this important, emerging area of cancer research.


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 = $191,052 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	3	11/15/2024	NON-COMPETING CONTINUATION	$191,052
														Subtotal = $191,052

Issue Date FY: 2024 ( Subtotal = $191,052 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	2	11/2/2023	NON-COMPETING CONTINUATION	$191,052
														Subtotal = $191,052

Issue Date FY: 2023 ( Subtotal = $191,052 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	1	11/22/2022	NEW	$191,052
														Subtotal = $191,052

Grand Total All Awards = $573,156

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The HDAC3 pathway in LKB1-mutant lung cancer and senescence

Award Number: K22CA251636

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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