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Mechanism of LSD1 Function and Its Therapeutic Application for Progressive Oral Malignancy

Award Number: R01DE031413
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Mechanism of LSD1 Function and Its Therapeutic Application for Progressive Oral Malignancy - Abstract Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase. Our work shows that LSD1 expression progressively increases with tumor grade and stage in clinical oral squamous cell carcinoma (OSCC). Our long- term goal is to evaluate LSD1 mechanism in progressive oral malignancy based on preliminary studies for therapeutic applications. Recent preliminary studies showed that conditional LSD1 deletion in the tongue epithelium during dysplasia reduced invasive pathological lesions, downregulated EGFR, YAP-induced signaling network, and Pd-L1 expression. Next, the topical application of LSD1 inhibitor during dysplasia prevented its progression to invasive phenotype, attenuated pathological lesions, expression of Hippo signaling effectors (Yap, Taz, Ccn2,) and immune checkpoints (Pd-1, and Pd-l1). LSD1 inhibitor sensitized OSCC to combinations with either YAP inhibitor, anti-PD-1, or anti-PD-L1 antibodies, limiting tumor progression in vivo. Thus, we showed for the first time that blocking LSD1 inhibits preneoplasia, a feed-forward loop during the progression of dysplasia to OSCC. Interestingly, LSD1 inhibition attenuates IL-6-JAK-STAT3 novel signaling identified in two independent studies 1) proteomics analysis of LSD knockout mice preneoplasia and 2) single-cell RNAseq analysis using LSD1 inhibitor. However, the mechanism of LSD1 function, its target cells in progressive oral malignancy, and how LSD1 promotes IL-6-JAK-STAT3 remain unclear. This knowledge gap prevents the targeted design of effective new epigenetic therapeutic strategies for OSCC. We hypothesize that (1) LSD1 upregulation during dysplasia reprograms oral tissue to invasive phenotype by acting on IL6 -signaling and induced cell types and (2) pharmacological attenuation of LSD1 reset epigenome to reverse progressive malignant preneoplasia to a noninvasive phenotype. Using clinically relevant animal models, this project is well- positioned to address the following Specific Aims: 1) to determine how upregulated LSD1 epigenetically reprogram dysplasia to promote IL6 network during progressive oral preneoplasia invasive phenotype; 2) to determine if LSD1 collaborates with YAP to promote IL6-JAK-STAT3 network induced invasive phenotype in preneoplasia, and 3) to determine the translational importance of pharmacological LSD1 inhibition reverse preneoplasia by inhibiting IL6-JAK-STAT3 signaling induced cancer stem and immune cells. The successful completion of the proposed project is expected to identify LSD1 and therapeutic application mechanisms in the IL6-JAK-STAT3 network, related stem cells, and immune cells. Finally, the study will determine if LSD1 a role in anti-PD-1 immunotherapy resistance and pharmacological LSD1 inhibition can attenuate feline OSCC for a potential application in veterinary and human medicine. Overall, the study will have a broader impact on future translational studies in human preneoplasia.


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 = $461,416 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	001	4	5/6/2025	NON-COMPETING CONTINUATION	$46,141
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	000	4	3/11/2025	NON-COMPETING CONTINUATION	$415,275
														Subtotal = $461,416

Issue Date FY: 2024 ( Subtotal = $610,781 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	003	3	6/19/2024	NON-COMPETING CONTINUATION	$42,759
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	001	3	1/16/2024	NON-COMPETING CONTINUATION	$481,057
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	002	3	1/18/2024	SUPPLEMENT FOR EXPANSION	$72,474
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	000	2	10/27/2023	SUPPLEMENT FOR EXPANSION	$14,491
														Subtotal = $610,781

Issue Date FY: 2023 ( Subtotal = $659,051 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	001	2	2/9/2023	NON-COMPETING CONTINUATION	$65,904
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	000	2	1/12/2023	NON-COMPETING CONTINUATION	$593,147
														Subtotal = $659,051

Issue Date FY: 2022 ( Subtotal = $570,216 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	000	1	3/9/2022	NEW	$570,216
														Subtotal = $570,216

Grand Total All Awards = $2,301,464

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Mechanism of LSD1 Function and Its Therapeutic Application for Progressive Oral Malignancy

Award Number: R01DE031413

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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