Discovering novel therapies for glioma patients

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

We made progress at both preclinical and clinical level for this project. Preclinically, we completed and published the preclinical studies to demonstrate that IDH-mutant gliomas have selective vulnerability to ZTR treatment. By conducting a high throughput drug screen, we pinpointed a specific vulnerability of IDH-mutant gliomas to zotiraciclib (ZTR). ZTR exhibited selective growth inhibition across multiple IDH-mutant glioma in vitro and in vivo models. Mechanistically, ZTR at low doses suppressed CDK9 and RNA Pol II phosphorylation in IDH-mutant cells, disrupting mitochondrial function and NAD+ production, resulting in oxidative stress. Integrated biochemical profiling of ZTR kinase targets and transcriptomics unveiled that ZTR-induced bioenergetic failure was linked to the suppression of PIM kinase activity. We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas. Clinically, we have completed the phase 1 part of the clinical trial 000860, A Phase I/II Study of Zotiraciclib for Recurrent Malignant Gliomas with Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations. In addition to identify the RP2D, we observed 2 objective response, suggesting the biological activity of ZTR in IDH-mutant gliomas in patients. Phase II study has started enrollment.