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The role of ANGEL2 in TP53-dependent tumor suppression

Award Number: K22CA279075
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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The role of ANGEL2 in TP53-dependent tumor suppression - Project Summary ANGEL2 is an RNA-binding protein (RBP), and member of the catabolite repression 4 (CCR4) family of proteins, which are involved in the modulation of mRNA stability and translation. With clinical significance, decreased ANGEL2 expression across 17 different cancer types is correlated with both poor overall and disease-free survival. However, the molecular mechanisms by which ANGEL2 modulates tumorigenesis have yet to be determined. Gene expression correlation analysis revealed a functional relationship between ANGEL2 and the tumor suppressor TP53. Consistently, ANGEL2 deficiency caused a substantial loss of TP53 expression and resulted in multicellular tumor spheroids adopting a stellate/invasive morphology. In addition, an ANGEL2-derived peptide increased TP53 expression and decreased multicellular tumor spheroid growth. TP53 is a transcription factor and stress sensor which plays an integral role in maintaining the genome. Inactivation of TP53 occurs in more than 50% of human cancers, and is a hallmark of tumor progression and chemoresistance. It is therefore widely recognized that loss of wild-type TP53 expression/function is a driver of tumor progression. Consequently, determining the key modulators of TP53 is paramount for the understanding of tumorigenesis and the development of the novel therapeutic approaches. This project aims to elucidate the role of ANGEL2 in TP53-dependent tumor suppression, and to determine if this pathway can be targeted to enhance wild-type TP53 expression and suppress tumor growth. Utilizing ANGEL2 knockout cell lines, coupled with xenograft and patient-derived organoid models, the effect of ANGEL2 on TP53 expression, and TP53-dependent tumor suppression will be determined. Moreover, the use of molecular and biophysical tools to design and modify ANGEL2-derived peptides to upregulate wild-type TP53 expression will be explored as a therapeutic approach for malignancies which carry wild-type TP53. These studies will guide the career development of Dr. Christopher Lucchesi by providing relevant knowledge and skills obtained through collaborations and courses in molecular and biophysical techniques, 3D-organoid tumor modeling, peptide drug design, translational research and leadership skills. Dr. Lucchesi will also profit from the wealth of available resources at UC Davis to equip him with the necessary skillsets to reach his career goals. Through training in this collaborative, ‘One Medicine’ environment, Dr. Lucchesi will be a competitive, independent investigator and a leader of a successful and productive research team.


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 = $194,408 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Research Manpower	000	3	3/6/2026	NON-COMPETING CONTINUATION	$194,408
														Subtotal = $194,408

Issue Date FY: 2025 ( Subtotal = $194,408 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Research Manpower	000	2	7/9/2025	NON-COMPETING CONTINUATION	$194,408
														Subtotal = $194,408

Issue Date FY: 2024 ( Subtotal = $194,408 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Research Manpower	000	1	3/11/2024	NEW	$194,408
														Subtotal = $194,408

Grand Total All Awards = $583,224

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The role of ANGEL2 in TP53-dependent tumor suppression

Award Number: K22CA279075

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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