TRSC-04 DE NOVO GTP SYNTHESIS IS A METABOLIC VULNERABILITY FOR THE INTERCEPTION OF BRAIN METASTASES Open Access

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.