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Genetic dependencies in KIAA1549-BRAF rearranged pediatric low-grade gliomas

Award Number: K99CA290163
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Genetic dependencies in KIAA1549-BRAF rearranged pediatric low-grade gliomas - Project Summary: Pediatric low-grade gliomas (pLGGs) typically harbor only a single oncogenic driver mutation. In most tumors this driver mutation is a fusion between the N-terminus of KIAA1549 and the C-terminus of BRAF. Many patients with these driver mutations respond to BRAF inhibitors, but several challenges remain in extending clinical benefit to all patients. One challenge is that there is often severe toxicity associated with these treatments which necessitates cessation of treatment. These clinical observations highlight a clear need to develop new therapeutic strategies to treat pLGG. We identified the two core members of the POMT complex (POMT1 and POMT2) as being selectively essential for the survival of KIAA1549:BRAF-dependent cells. The POMT complex is necessary for O-mannosylation of secreted and transmembrane proteins, which is striking because KIAA1549 is reported to be highly mannosylated. It was originally hypothesized that the KIAA1549:BRAF fusion activates BRAF by truncating its N-terminal negative regulatory domains, but my preliminary data suggests that the KIAA1549 portion of the fusion is also necessary for activating BRAF. The primary goals of this proposal are to more broadly understand how the KIAA1549:BRAF fusion is activated, and to understand why the POMT complex is a selective dependency in KIAA1549:BRAF-dependent cells. In Aim 1 I will test the hypothesis that POMT enzymatic activity is necessary for the survival of KIAA1549:BRAF rearranged pLGG. In Aim 2 I will test the hypothesis that O-mannosylation of KIAA1549:BRAF is necessary for oncogenic signaling. And in Aim 3 I will test the hypothesis that cleavage of KIAA1549:BRAF by Furin is necessary for RAF activation. During this proposal I will also engage in a range of activities designed to enhance my scientific training. I will attend and present at multiple national and international conferences and will participate in retreats and networking events with other pediatric oncology groups. My ultimate career goal is to establish my own independent research laboratory focused on pediatric neurooncology. The training I receive through this fellowship is a necessary step towards this goal.


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 = $143,788 )
2025	2025	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	000	1	1/24/2025	NEW	$143,788
														Subtotal = $143,788

Grand Total All Awards = $143,788

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Genetic dependencies in KIAA1549-BRAF rearranged pediatric low-grade gliomas

Award Number: K99CA290163

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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