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Defining the β-catenin/CBP-catenin/CBP axis in head and neck cancer

Award Number: R01DE030350
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: 12/07/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Defining the β-catenin/CBP-catenin/CBP axis in head and neck cancer - Head and neck squamous cell carcinoma (HNSCC) is a devastating malignancy associated with severe morbidity, high mortality and limited treatment options. The main subsite of HNSCC is the oral cavity, where the disease presents primarily as tobacco- and alcohol-associated HPV(-) oral squamous cell carcinoma (OSCC). Despite great progress in the understanding of genomic alterations in OSCC, the molecular details underlying the progression of non-invasive oral lesions to advanced disease with lymph node metastasis remain poorly understood. To gain insights into the mechanisms that contribute to OSCC progression to metastasis we have studied the interaction between nuclear β-catenin and cAMP-response element-binding (CREB)-binding protein (CBP) in OSCC by applying our newly developed computational methodologies coupled with genomic, epigenetic, molecular, biochemical and functional analyses. Our published and preliminary studies show that inhibition of β-catenin/CBP activity with small molecule antagonists, ICG-001 and E7386, in a panel of OSCC cell lines inhibits cell proliferation and mesenchymal phenotype while inducing cellular differentiation. Similarly, inhibition of β-catenin/CBP signaling in human OSCC cell line-derived tumor xenografts in nude mice inhibits tumor growth and metastasis and abrogates rapid metastases driven by subpopulations of OSCC stem cell-like cells, or cancer stem cells (CSCs), in embryonic zebrafish. Our recent global chromatin immunoprecipitation followed by sequencing (ChIPseq) studies show that β-catenin/CBP collaborates with the histone methyltransferase, MLL1, to promote global H3K4 trimethylation (H3K4me3) at transcription start sites (TSS) of numerous CSC genes. This finding is supported by our recent genomic analyses based on RNAseq and scRNAseq data showing that β-catenin/CBP activity is associated with aggressive cell states, including CSCs. Preliminary analyses also suggest that β-catenin/CBP complexes include the Hippo pathway effectors YAP and TAZ (YAP/TAZ), which, like β-catenin, are associated with resistance to both chemotherapy and cetuximab in HNSCC (19,20). Using well characterized OSCC cell lines, we integrated gene expression signatures associated with the inhibition of the β-catenin/CBP axis with OSCC data from The Cancer Genome Atlas (TCGA) to show that β-catenin/CBP activity is associated with progressive disease and reduced patient survival. Building on these collective findings we hypothesize that aberrant activation of β-catenin/CBP signaling underlies the expansion CSCs during HNSCC progression to metastatic disease and that its antagonism may inhibit advanced disease. This hypothesis will be tested in two aims that will: 1) define the role of the β-catenin/CBP axis in HNSCC progression to advanced disease; and 2) determine the molecular mechanisms underlying β-catenin/CBP activity in the induction of CSC phenotypes. Our studies will generate a dynamic integrated map aligning β-catenin-CBP- activity with distinct aggressive cell states and their associated in gene signatures, signaling networks and protein assemblies and provide a rationale for the development of new treatment strategies to combat this malignancy.


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 = $554,143 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	001	5	5/5/2025	NON-COMPETING CONTINUATION	$55,415
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	000	5	11/14/2024	NON-COMPETING CONTINUATION	$498,728
														Subtotal = $554,143

Issue Date FY: 2024 ( Subtotal = $633,640 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	001	4	6/12/2024	NON-COMPETING CONTINUATION	$51,727
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	000	4	11/21/2023	NON-COMPETING CONTINUATION	$581,913
														Subtotal = $633,640

Issue Date FY: 2023 ( Subtotal = $669,143 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	002	3	2/9/2023	NON-COMPETING CONTINUATION	$66,915
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	001	3	11/22/2022	NON-COMPETING CONTINUATION	$602,228
2023	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	000	1	10/31/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $669,143

Issue Date FY: 2022 ( Subtotal = $639,175 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	002	2	4/20/2022	NON-COMPETING CONTINUATION	$58,109
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	000	2	11/5/2021	NON-COMPETING CONTINUATION	$581,066
2022	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	001	1	11/29/2021	NEW	$0
														Subtotal = $639,175

Issue Date FY: 2021 ( Subtotal = $727,424 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	001	1	12/8/2020	NEW	$0
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	000	1	12/7/2020	NEW	$563,548
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Oral Diseases and Disorders Research	002	1	8/5/2021	SUPPLEMENT FOR EXPANSION	$163,876
														Subtotal = $727,424

Grand Total All Awards = $3,223,525

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Defining the β-catenin/CBP-catenin/CBP axis in head and neck cancer

Award Number: R01DE030350

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: 12/07/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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