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Targeting SMARCA2 as a therapeutic strategy in SMARCA4 mutant lung cancer

Award Number: R01CA272945
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Targeting SMARCA2 as a therapeutic strategy in SMARCA4 mutant lung cancer - Project Summary Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. Recent reports and our own data have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4. However, identifying selective inhibitors of SMARCA2 has been challenging. Hence, we have developed novel SMARCA2 degrading small molecules based on the proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. We further showed that YD23 selectively inhibits growth of SMARCA4 mutant lung cancer cells. Mechanistically, we showed that YD23 induces changes in chromatin accessibility only in SMARCA4 deficient cells. Taking these observations together, we hypothesize that SMARCA2 degradation using YD23 is an attractive therapeutic strategy with promising therapeutic index in lung cancers with inactivating mutations in SMARCA4. The major objective of the proposed study is to provide preclinical evidence to guide future development of YD23 (or its analogs) in patients with SMARCA4 mutant lung cancer. While we have shown marked sensitivity of SMARCA4 mutant lung cancer cell lines to YD23, we still do not know the detailed mechanistic basis for this activity. Hence, we intend to perform gene expression, epigenetic and chromatin accessibility studies followed by integrative analysis to triangulate on direct target genes whose chromatin landscape is altered by presence or absence of SMARCA2 in SMARCA4 mutant cancer cells. While our in vitro cancer cell growth inhibitory studies are encouraging, a systematic exploration in vivo using various orthogonal model systems is required to aid the preclinical development of SMARCA2 degraders. Thus, we propose to determine the potential of YD23 mediated SMARCA2 degradation in SMARCA4 mutant xenograft and patient derived xenograft (PDX) model systems. Due to the unique microenvironment of lung cancer we will also test efficacy of YD23 in GEM models of lung cancer. Finally, SMARCA2 as a synthetic lethal partner of SMARCA4 has so far been described by in vitro experiments. In vivo genetic validation is critical to unequivocally demonstrate the requirement of a gene of interest in the development of a genetically defined subtype of cancer. Thus, we aim to perform CRISPR-Cas9 mediated Smarca2 genetic ablation to determine the extent of its involvement in the development and biology of Smarca4 mutant GEM models. In conclusion, our study is expected to provide mechanistic insight into the synthetic lethal genetic relationship between SMARCA2 and SMARCA4 and lay the foundation for future clinical development of SMARCA2 degraders as therapeutics.


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 = $537,633 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	6/11/2025	NON-COMPETING CONTINUATION	$537,633
														Subtotal = $537,633

Issue Date FY: 2024 ( Subtotal = $510,751 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	6/6/2024	NON-COMPETING CONTINUATION	$510,751
														Subtotal = $510,751

Issue Date FY: 2023 ( Subtotal = $526,882 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	8/1/2023	NON-COMPETING CONTINUATION	$526,882
														Subtotal = $526,882

Issue Date FY: 2022 ( Subtotal = $537,633 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	8/15/2022	NEW	$537,633
														Subtotal = $537,633

Grand Total All Awards = $2,112,899

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Targeting SMARCA2 as a therapeutic strategy in SMARCA4 mutant lung cancer

Award Number: R01CA272945

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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