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Deciphering non-canonical translation in high risk medulloblastoma

Award Number: K08CA263552
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Deciphering non-canonical translation in high risk medulloblastoma - PROJECT SUMMARY/ABSTRACT Children with the Group 3 subtype of medulloblastoma experience poor outcomes, with nearly 50% mortality despite intensive treatment regimens. Thus, new treatment options are desperately needed. While prior efforts have studied the ~20,000 known protein-coding genes in medulloblastoma, I have investigated >2,000 non- canonical proteins that were previously excluded. I have discovered that MYC-driven, Group 3 medulloblastoma cells are dependent on an upstream open reading frame (uORF) encoded within the ASNSD1 5’ untranslated region. Perturbation of this uORF impacted the MYC cellular program, and it bound to the prefoldin complex, which is critical for gene regulation. These findings provide a rationale to study ASNSD1 uORF as an oncogenic driver in medulloblastoma and suggest that non-canonical proteins are a fertile territory for cancer discovery. To advance ASNSD1 uORF as a potential therapeutic target, this proposal will pursue two specific aims in the context of Group 3 medulloblastoma: (1) to validate ASNSD1 uORF in advanced cell line and mouse models of medulloblastoma and (2) to confirm the role of the ASNSD1-prefoldin complex interaction in medulloblastoma. I am an Instructor in Pediatric Neuro-oncology with at least 80% protected time for research, who is committed to uncovering medulloblastoma disease mechanisms to advance patient care. My career goal is to become an independent physician-scientist with research focused on novel medulloblastoma therapeutic targets. The purpose of this career development award is to enable me to gain specific research training in medulloblastoma mouse model systems, proteomics techniques and computational analysis. I seek to use these research skills to advance my work studying non-canonical proteins as novel medulloblastoma vulnerability genes. I have chosen an outstanding mentorship team of Drs. Todd Golub and Pratiti Bandopadhayay for this proposal. Dr. Golub is an authority on the discovery of therapeutic targets and brings over 20 years of experience in mentoring K08-level physician scientists. I have selected Dr. Bandopadhayay as a co-mentor because she is an innovator in medulloblastoma and deep knowledge of medulloblastoma model systems. My advisory committee includes experts reflecting key areas of my training plan: Drs. Steve Gygi (proteomics), Scott Pomeroy (medulloblastoma), Ernest Fraenkel (computational biology) and Kim Stegmaier (pediatric genomics). Both my mentor, co-mentor, and advisory committee are committed to my research training, career development and growth into an independent physician-scientist at the conclusion of this award. I will train at the Dana-Farber Cancer Institute and the Broad Institute, which are both outstanding institutions with unique research opportunities. This training environment provides numerous opportunities for me to benefit from didactic coursework relevant to this award, as well as participate in world-class research conferences. With the mentored research and career development offered through this K08 award, I will be ideally suited to establish my independent career as a physician-scientist in pediatric neuro-oncology.


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 = $233,318 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Research Manpower	000	4	8/14/2025	NON-COMPETING CONTINUATION	$233,318
														Subtotal = $233,318

Issue Date FY: 2024 ( Subtotal = $230,585 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Research Manpower	002	3	7/24/2024	NON-COMPETING CONTINUATION	$230,585
2024	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Research Manpower	001	2	10/27/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$123,766
2024	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	1	10/27/2023	NEW	-$123,766
														Subtotal = $230,585

Issue Date FY: 2023 ( Subtotal = $232,092 )
2023	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	1	7/26/2023	NEW	$0
2023	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Research Manpower	001	2	7/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$232,092
														Subtotal = $232,092

Issue Date FY: 2022 ( Subtotal = $226,800 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	1	8/23/2022	NEW	$226,800
														Subtotal = $226,800

Grand Total All Awards = $922,795

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Deciphering non-canonical translation in high risk medulloblastoma

Award Number: K08CA263552

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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