RESUMEN
Isocitrate dehydrogenase (IDH)-mutant gliomas have distinctive metabolic and biological traits that may render them susceptible to targeted treatments. Here, by conducting a high-throughput drug screen, we pinpointed a specific susceptibility 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, causing 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. These findings prompted a clinical trial evaluating ZTR in IDH-mutant gliomas towards precision medicine ( NCT05588141 ). Highlights: Zotiraciclib (ZTR), a CDK9 inhibitor, hinders IDH-mutant glioma growth in vitro and in vivo . ZTR halts cell cycle, disrupts respiration, and induces oxidative stress in IDH-mutant cells.ZTR unexpectedly inhibits PIM kinases, impacting mitochondria and causing bioenergetic failure.These findings led to the clinical trial NCT05588141, evaluating ZTR for IDH-mutant gliomas.
RESUMEN
Background: Deletions or loss-of-function mutations in phosphatase and tensin homolog (PTEN) are common in glioblastoma (GBM) and have been associated with defective DNA damage repair. Here we investigated whether PTEN deficiency presents a vulnerability to a simultaneous induction of DNA damage and suppression of repair mechanisms by combining topoisomerase I (TOP1) and PARP inhibitors. Methods: Patient-derived GBM cells and isogenic PTEN-null and PTEN-WT glioma cells were treated with LMP400 (Indotecan), a novel non-camptothecin TOP1 inhibitor alone and in combination with a PARP inhibitor, Olaparib or Niraparib. RNAseq analysis was performed to identify treatment-induced dysregulated pathways. Results: We found that GBM cells lacking PTEN expression are highly sensitive to LMP400; however, rescue of the PTEN expression reduces sensitivity to the treatment. Combining LMP400 with Niraparib leads to synergistic cytotoxicity by inducing G2/M arrest, DNA damage, suppression of homologous recombination-related proteins, and activation of caspase 3/7 activity significantly more in PTEN-null cells compared to PTEN-WT cells. LMP400 and Niraparib are not affected by ABCB1 and ABCG2, the major ATP-Binding Cassette (ABC) drug efflux transporters expressed at the blood-brain barrier (BBB), thus suggesting BBB penetration which is a prerequisite for potential brain tumor treatment. Animal studies confirmed both an anti-glioma effect and sufficient BBB penetration to prolong survival of mice treated with the drug combination. Conclusions: Our findings provide a proof of concept for the combined treatment with LMP400 and Niraparib in a subset of GBM patients with PTEN deficiency.
RESUMEN
Most tumors, including brain tumors, are sporadic. However, a small subset of CNS tumors are associated with hereditary cancer conditions like Lynch Syndrome (LS). Here, we present a case of an oligodendroglioma, IDH-mutant and 1p/19q-codeleted, and LS with a germline pathogenic PMS2 mutation. To our knowledge, this has only been reported in a few cases in the literature. While the family history is less typical of LS, previous studies have indicated the absence of a significant family history in patient cohorts with PMS2 mutations due to its low penetrance. Notably, only a handful of studies have worked on characterizing PMS2 mutations in LS, and even fewer have looked at these mutations in the context of brain tumor development. This report aims to add to the limited literature on germline PMS2 mutations and oligodendrogliomas. It highlights the importance of genetic testing in neuro-oncology.