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Protein O' Mannosylation as a therapeutic vulnerability in KIAA1549-BRAF-driven pediatric low-grade glioma

Award Number: R01CA303137
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/05/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Protein O' Mannosylation as a therapeutic vulnerability in KIAA1549-BRAF-driven pediatric low-grade glioma - Abstract Pediatric low-grade gliomas (pLGGs) are the most frequent solid tumor of childhood and include Pilocytic Astrocytomas (PAs). Approximately 75% of PAs result from a single driver event: a rearrangement between BRAF and the uncharacterized protein KIAA1549. The KIAA1549-BRAF fusion protein drives glioma formation through unopposed activation of the BRAF kinase, largely thought to result from loss of its N-terminal regulatory domains. However, the role of KIAA1549 in facilitating gliomagenesis is completely unknown. Our team has generated preliminary data that, among all genes in the genome, cells expressing KIAA1549- BRAF are highly and specifically dependent on POMT1, POMT2, and other members of the Protein Omannosyltransferase (POMT) complex—a complex that regulates O-mannosylation, a form of glycosylation. This is intriguing because, although little is known about KIAA1549, it has been identified as among the most highly mannosylated proteins in the proteome. These findings lead us to hypothesize that POMT-mediated Omannosylation of KIAA1549 in KIAA1549-BRAF fusions is necessary for the fusion protein to promote gliomagenesis, thereby indicating POMT as a novel and druggable therapeutic target. Our proposal incorporates the use of mouse studies to validate therapeutic potential of POMT-suppression and other targets, and to systematically evaluate potential toxicity associated with POMT suppression across the developmental spectrum, including pediatric mice. These mouse studies are essential as no in vitro or predictive computational model is yet able to evaluate and/or predict these phenotypes taking into context the glioma microenvironment and how this is modulated across development. Understanding toxicities predicted to occur with suppression of the POMT complex in young mice is vital to inform drug development for young children. This Research Program leverages existing collaborations between the PIs Drs. Beroukhim and Bandopadhayay in Boston, USA with Drs. Adnan Halim and Hiren Joshi at the University of Copenhagen. Our proposal is focused on glycosylation of KIAA1549 by POMT as a necessary step to activate the KIAA1549-BRAF fusion for oncogenesis. Drs. Halim and Joshi were the first to publish that KIAA1549 is a prominent substrate of POMT, undergoing substantial O-mannosylation, and continue to study posttranslational modifications of KIAA1549 including glycosylation and its effects on cleavage of the protein. The expertise of Drs. Halim and Joshi, and their collaboration with Drs. Beroukhim and Bandopadhayay will help ensure successful completion of the Research Program outlined in this proposal. No NIH funding is requested to support this collaboration, and no funds will be transferred to the University of Copenhagen. The Research Program outlined in this application will dissect the mechanisms by which POMT mediates KIAA1549-BRAF associated oncogenesis and will identify strategies through which these can be leveraged in novel therapeutic approaches for children with the most common brain tumor of childhood.


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 = $721,653 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	1	6/9/2026	NEW	$721,653
														Subtotal = $721,653

Grand Total All Awards = $721,653

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Protein O' Mannosylation as a therapeutic vulnerability in KIAA1549-BRAF-driven pediatric low-grade glioma

Award Number: R01CA303137

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/05/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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