Isocitrate dehydrogenase

Now, where is this gonna be leading into all this dyslipidemia? Well, you can see already that we're involving intermediary metabolism.

So for example, inhibition of the TET-mediated DNA methylation process, which can occur because of a mutant isocitrate dehydrogenase.

This is where 2-hydroxyglutarate, which can be generated from alpha-ketoglutarate because of a mutant IDH1,2, will competitively inhibit the function of alpha-ketoglutarate-dependent enzymes.

Now, I didn't mention, now I will, the TET enzyme requires alpha-ketoglutarate.

So in fact, the TET enzyme is an alpha-ketoglutarate-dependent enzyme, such that the TET2 and then the histone demethylases all function in a coordinated manner.

include the JMJs, the FBXs, and the KDM2s, three different basically families of histone demethylases.

So this occurs because, again, alpha-ketoglutarate naturally is required for TET2, to take 5-methylcytosine and generate back cytosine via base excision, as I mentioned before.

But because isocitrate converted to alpha-ketoglutarate and then a mutant IDH 1, 2, will generate that 2-hydroxyglutarate, which will inhibit competitively the TET2 enzyme because it's blocking alpha-ketoglutarate.

They traditionally were graded histologically, which means it was primarily by what they looked like under a microscope.

With more advanced technology, though, we have also incorporated molecular markers to define the grading, particularly if they have a mutation in an enzyme involved in the cell metabolism called isocitrate dehydrogenase, or IDH.

Hence, you may see tumors, particularly for astrocytoma, as described as IDH wild type, which means the absence of the mutation, or IDH mutated, which is having the mutation.

Thank you.

And Dr. Bovee, if a patient is diagnosed with a glioma, what types of treatment are commonly used for it?

And it's best in patients under the age of 60 with less than 5% blasts and if they have PNH clone that is positive.

And then IDH mutated lower risk after failure of ESAs, you can also consider the IDH1 inhibitor ivosidenib or enasidenib, which is a IDH2 inhibitor.

Definitely.

So I have to laugh because even though we've taken our boards now five years ago, when you, when I read or when you read the lenalidomide for deletion 5q low-risk MDS, I immediately thought, "I know that because there was a question on it." [laughs]

So that's azacitidine, which is 75 milligram per meter squared for seven days every four weeks, category one, and it's the only agent with a phase 3 survival benefit, or decitabine 20 milligrams per meter squared for five days every four weeks for at least four to six cycles.

And then there's also oral decitabine, cedirotinib, which is an acceptable substitute, uh, for the IV decitabine.

And then venetoclax may be added to the hypomethylating backbone in select patients, as well as IDH inhibitors, the ones we just talked about, ivosidenib, as well as here is olutasidenib for mutated IDH1, and then enasidenib for mutated IDH2.

And then transplant-eligible patients may go directly to transplant or receive hypomethylating chemo agents to bridge to get the blast under 5%.

And so we have a product called NeuroInsight that's for IDH1, IDH2.

IDH2 doesn't have a really good IHC around it, so immediately we would add 15% market share to a couple companies that already have IDH drugs out.

And our initial studies in that show that we're better than the IHC, very quickly.

And my father passed away of aglemo brain cancer.

It doesn't require, you know, uh, really, um, the personnel to run an NGS type test.

So I think over time with EGFR, I think that's a really good marker.

IDH and brain cancer is a fantastic marker that we have a really great initial test for.

That could potentially be the first CDX type test is the IDH one for us at Imaginomics.

And after cancer has unfortunately grown on chemotherapy, that's where these would come into play.

And there are always things emerging that are specific to the sarcoma itself so for example in chondrosarcoma there are the what's common is something called an IDH mutation and we sometimes we're trying to investigate whether we can use drugs called IDH inhibitors and then something very specific to chondros is something we've got something called a DR5 agonist or DEF receptor 5 agonist and we're starting to see really promising results with that so things are always evolving and changing now that's not a medicine we have available at the moment But that's, we think, we hope will come in the future.

Liz, just before, Travis asked about the side effects of the chemo, but are there any possible long-term side effects of treatment for these sarcomas?

Yeah, absolutely.