VIDEO: Evolution of targeted therapies for treatment of gliomas

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As I mentioned, you know, the most common primary malignant brain tumor, glioblastoma or IDH wild type glioblastoma, really has a whole spectrum of genetic alterations in it. So the use of a single targeted drug is gonna be very challenging. None of them have really worked yet in glioblastoma.

But again, if you go back to the other end of the spectrum, an example I will use is pediatric low grade astrocytoma, which is a low grade tumor, less genetically complex, one of the most common tumors of childhood. Well, it turns out that there are particular genetic alterations in that pediatric low grade astrocytoma that are what we call actionable. In other words, they're felt to be oncogenic drivers. They enable the tumor to survive, to grow, to infiltrate.

But by targeting that you could turn all those off and potentially turn the tumor off or potentially shrink the tumor. So one of those drivers is a genetic alteration known as a RAF truncation fusion. It's a particular genetic alteration that is seen at about 60 to 70% of pediatric low grade astrocytomas and is an oncogenic driver. And we and others have done studies showing that a particular targeted therapy known as Tovorafenib, which targets that RAF alteration, is very effective. And in most of the kids with this kind of tumor, when given this single agent will have shrinkage of the tumor.

And in fact, that drug was approved, Tovorafenib, for RAF altered pediatric low grade astrocytomas in 2024, this year. So that is now an FDA approved treatment for pediatric low grade astrocytoma with a RAF alteration. The last one I'll comment on is we see in higher grade astrocytomas grades two, three, and even four, is an IDH mutation. And IDH stands for iso citrate dehydrogenase. It's a normal enzyme of our sort of Krebs cycle, so metabolic cycle, very important fundamental in cell survival. Anyway, there's a mutation in that IDH gene in 70 to 80% of astrocytomas in young adults, and even in about 10% of older adults who have that mutation.

It's felt to be an oncogenic driver, again, enabling the cell to grow, infiltrate, survive. And by targeting that you can again, begin to turn off some of that. We've now seen just very recent data with a drug, an IDH inhibitor, that using that drug in an IDH mutant low glioma is very effective. It can delay the time to tumor progression. And we are hopeful that this year we will see FDA approval of that drug so that we can now begin to use that drug in the clinic. So those are examples of, you know, mutations that are drivers that are actionable, that drugs have been developed to target those. Studies have been completed and we have one on FDA approved now, and we hope the other one will be FDA approved very soon.