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Therapeutic degradation of Capicua (CIC) fused oncoproteins in undifferentiated sarcomas

Award Number: R37CA255453
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/17/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Therapeutic degradation of Capicua (CIC) fused oncoproteins in undifferentiated sarcomas - PROJECT SUMMARY/ABSTRACT The CIC-DUX4 fusion oncoprotein is the molecular hallmark of a highly lethal subset of undifferentiated sarcomas that affects children, adolescents, and young adults (AYA). We have recently revealed critical transcriptional programs downstream of CIC-DUX4 that drive malignant phenotypes, including tumor growth and metastasis. Additionally, recent studies demonstrate that Capicua (CIC) protein expression is directly modulated by the mitogen-activated protein kinase (MAPK)-signaling pathway. The long-term goal of our laboratory is to identify and dissect the critical molecular pathways that regulate fusion oncoprotein stability and expression in human sarcoma. Our studies will reveal fusion oncoprotein-specific vulnerabilities that can facilitate precision-based therapeutic design to improve outcomes for patients with universally lethal forms of sarcomas. The objective of this proposal is to fuse our expertise in Capicua (CIC) biology and MAPK signaling to develop the first precision-based therapeutic approach for CIC-DUX4 sarcomas. We hypothesize, that genetic or pharmacologic MAPK activation will lead to the degradation of the CIC-DUX4 oncoprotein. Our rationale is based on our prior studies demonstrating MAPK-mediated regulation of wild-type (non-fused) CIC protein expression in the context of human cancer. Our specific aims will test the following hypotheses: (Aim 1) human ERK physically interacts with nuclear CIC-DUX4; (Aim 2) MAPK-ERK pathway activation decreases CIC-fused oncoprotein stability, leading to degradation; and (Aim 3) pharmacologic activation of the MAPK pathway decreases tumor cell survival through rapid degradation of the CIC-DUX4 fusion oncoprotein. The significance of these findings are highly impactful, as there are no effective therapeutic strategies to target CIC- DUX4 sarcomas, which remain lethal in the metastatic setting. Our proposal is innovative because we are leveraging our expertise in MAPK-signaling, transcription factor fusions, and Capicua biology to develop a precision-based therapeutic approach to directly target and degrade a lethal fusion oncoprotein in sarcoma, an unmet scientific and clinical need.


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 = $369,431 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$36,943
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	000	5	4/25/2025	NON-COMPETING CONTINUATION	$332,488
														Subtotal = $369,431

Issue Date FY: 2024 ( Subtotal = $369,431 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	000	4	5/13/2024	NON-COMPETING CONTINUATION	$369,431
														Subtotal = $369,431

Issue Date FY: 2023 ( Subtotal = $444,667 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	002	3	9/14/2023	NON-COMPETING CONTINUATION	$7,388
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	001	3	8/8/2023	SUPPLEMENT FOR EXPANSION	$75,236
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	3	5/9/2023	NON-COMPETING CONTINUATION	$362,043
														Subtotal = $444,667

Issue Date FY: 2022 ( Subtotal = $369,431 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	001	2	8/31/2022	NON-COMPETING CONTINUATION	$7,388
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	2	5/25/2022	NON-COMPETING CONTINUATION	$362,043
														Subtotal = $369,431

Issue Date FY: 2021 ( Subtotal = $369,431 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	1	6/17/2021	NEW	$369,431
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	001	1	9/14/2021	NEW	$0
														Subtotal = $369,431

Grand Total All Awards = $1,922,391

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Therapeutic degradation of Capicua (CIC) fused oncoproteins in undifferentiated sarcomas

Award Number: R37CA255453

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/17/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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