[R01] Protein O' Mannosylation as a therapeutic vulnerability in KIAA1549-BRAF-driven pediatric low-grade glioma
Ente: National Cancer Institute
Scadenza: 2031-05-31
Importo max: 721.653 EUR
Paese: US
Descrizione
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
Istituzione: DANA-FARBER CANCER INST
PI: RAMEEN BEROUKHIM, Pratiti Bandopadhayay
Progetto: 1R01CA303137-01A1
Settori: National Cancer Institute
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