Yes, this is sort of switching gears, but also for synthetic lethalities. So loss of the MTAP gene confers synthetic lethality to PRMT5 inhibitors. This is currently being investigated in multiple phase one slash two trials, predominantly in non-small cell lung cancer and pancreatic cancer. But at our institution we have a whole genome sequencing program going on since 2013 and from 2021 we did whole genome sequencing before that whole exome sequencing...
Yes, this is sort of switching gears, but also for synthetic lethalities. So loss of the MTAP gene confers synthetic lethality to PRMT5 inhibitors. This is currently being investigated in multiple phase one slash two trials, predominantly in non-small cell lung cancer and pancreatic cancer. But at our institution we have a whole genome sequencing program going on since 2013 and from 2021 we did whole genome sequencing before that whole exome sequencing. So we are able to confidently call the MTAP deletions on gene level and actually all the way down to the exon granularity level, which may have some importance since if you have just an exon level deletion of the MTAP gene, this may reduce the sensitivity to PRMT5 inhibition. Yeah, but that’s a whole other story. So for glioma, which we predominantly looked at in our cohort, which is rather large, 145 patients, which is to the best of our knowledge, the largest single center cohort here for MTAP deletions in CNS tumors, we found that for these 145 patients, roughly 40% had the biallelic MTAP deletions, which is sort of in accordance with the previous data. Next up, so these patients could in theory be eligible for a PRMT5 inhibitor trial. But then we also looked into the co-mutational landscape of these tumors because some of these tumors actually harbor some other actionable alterations. And we did find KRAS mutations, quite a few IDH1 mutations in the astrocytomas, the NF1 or PIK3CA mutations. So this could hopefully inspire others to go down to look into combination therapies to combine the PRMT5 inhibitors with like a PIK3CA inhibitor or a RAS inhibitor in this population of CNS tumors with a highly unmet need for treatment.
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