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A Cereblon signaling network in Wnt-driven cancers

Award Number: R01CA281002
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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A Cereblon signaling network in Wnt-driven cancers - A Cereblon Signaling Network in Wnt-driven Cancers Abstract The long-term objective of this study is to investigate how Cereblon (CRBN) regulates the Wnt signal transduction pathway and to demonstrate how this can be exploited to target Wnt-driven colorectal cancers (CRCs). Wnt signaling is essential for intestinal stem cell maintenance and aberrant activation of this pathway drives the initiation and progression of nearly all CRCs. To date, no drugs that inhibit the Wnt pathway have been FDA- approved, partly due to the lack of druggable targets that can bypass common Wnt pathway mutations in CRC. In a conceptual breakthrough, our recently published findings reveal that Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase that is a drug target in hematological malignancies, plays a critical role in Wnt signal transduction. We found that CRBN promotes the degradation of a subset of substrates, including Casein kinase 1α (CK1α), a negative regulator of Wnt signaling and a key component of the β-Catenin destruction complex. Moreover, Wnt stimulation induces the interaction of CRBN with CK1α to promote its ubiquitination and degradation. Furthermore, we showed that the role of CRBN in Wnt signaling is conserved in human cells, mouse intestinal organoids, zebrafish, and Drosophila. These studies demonstrate the first endogenous mechanism of CRBN regulation and provide a novel means of controlling Wnt pathway activity, with relevance for animal development and disease. The goal of this project is to use in vitro, ex vivo, and in vivo approaches to gain a better understanding of how the clinically relevant anti-cancer target, CRBN, promotes Wnt signal transduction. The three specific aims are to: 1) Identify the mechanisms by which Wnt stimulation activates CRBN; 2) Identify Wnt-stimulated CRBN interactors that regulate tumorigenesis; and 3) elucidate the role of CRBN in Wnt-dependent cancer progression. Because CRBN is a well-studied target for the development of drugs to treat hematological malignancies, the knowledge gained from this study will aid in the development of more selective small molecules as well as suggest innovative treatment strategies for CRC and other Wnt-driven cancers.


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: 2026 ( Subtotal = $655,614 )
2026	2026	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	000	4	3/5/2026	NON-COMPETING CONTINUATION	$655,614
														Subtotal = $655,614

Issue Date FY: 2025 ( Subtotal = $655,614 )
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	000	3	2/14/2025	NON-COMPETING CONTINUATION	$590,053
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	001	3	6/2/2025	NON-COMPETING CONTINUATION	$65,561
														Subtotal = $655,614

Issue Date FY: 2024 ( Subtotal = $622,834 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$32,781
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	000	2	1/18/2024	NON-COMPETING CONTINUATION	$590,053
														Subtotal = $622,834

Issue Date FY: 2023 ( Subtotal = $687,613 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	000	1	3/10/2023	NEW	$687,613
														Subtotal = $687,613

Grand Total All Awards = $2,621,675

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A Cereblon signaling network in Wnt-driven cancers

Award Number: R01CA281002

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/10/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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