
==== Front
Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae090.132
vdae090.132
Final Category: Translational Science
AcademicSubjects/MED00300
AcademicSubjects/MED00310
TRSC-04 DE NOVO GTP SYNTHESIS IS A METABOLIC VULNERABILITY FOR THE INTERCEPTION OF BRAIN METASTASES
Kieliszek Agata McMaster University, Hamilton, Canada

Mobilio Daniel McMaster University, Hamilton, Canada

Bassey-Archibong Blessing McMaster University, Hamilton, Canada

Johnson Jarrod McMaster University, Hamilton, Canada

Piotrowski Mathew McMaster University, Hamilton, Canada

Aghaei Nikoo McMaster University, Hamilton, Canada

Escudero Laura McMaster University, Hamilton, Canada

Gwynne William McMaster University, Hamilton, Canada

de Araujo Elvin University of Toronto, Toronto, Canada

Sedighi Abootaleb University of Toronto, Toronto, Canada

Chafe Shawn McMaster University, Hamilton, Canada

Zhai Kui McMaster University, Hamilton, Canada

Zhang Cunjie University of Toronto, Toronto, Canada

Quaile Andrew University of Toronto, Toronto, Canada

McKenna Dillon McMaster University, Hamilton, Canada

Subapanditha Minomi McMaster University, Hamilton, Canada

Gunning Patrick University of Toronto, Toronto, Canada

Tokar Tomas University of Toronto, Toronto, Canada

Montenegro-Burke J Rafael University of Toronto, Toronto, Canada

Venugopal Chitra McMaster University, Hamilton, Canada

Magolan Jakob McMaster University, Hamilton, Canada

Singh Sheila McMaster University, Hamilton, Canada

8 2024
02 8 2024
02 8 2024
6 Suppl 1 2024 SNO/ASCO CNS Metastases Conference i40i40
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

Patients with brain metastases (BM) face a 90% mortality rate within one year of diagnosis and the current standard of care is mainly palliative. Targeting BM-initiating cells (BMIC) is a feasible strategy to treat BM, but druggable targets are still very limited. Here, we applied Connectivity Map analysis to lung-, breast-, and melanoma- pre-metastatic BMIC gene expression signatures and identified inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo GTP synthesis pathway, as a target for BM. We showed that pharmacological and genetic perturbation of IMPDH attenuates BMIC proliferation in vitro and the formation of BM in vivo. Furthermore, we used medicinal chemistry to develop novel brain penetrant IMPDH-inhibitors with enhanced in vivo efficacy. Metabolomic analyses and CRISPR knockout studies confirmed that de novo GTP synthesis is a potent metabolic vulnerability in BM. Overall, our work employed a phenotype-guided therapeutic strategy to uncover IMPDH as a relevant target for attenuating BM outgrowth, which may provide an alternative treatment strategy for patients who are otherwise limited to palliation.
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pmc
