NorthWest Biotherapeutics Inc (NWBO)

[Lykiri]

Johnnygogo,

I found this summary on a brain tumor patient forum. Hope that helps.

Methylation is driven by two genes: IDH-1 and MGMT Promoter. These two work cooperatively with one another to produce methylation. So, you can have these combinations:

IDH-1 negative (i.e., unmutated) + MGMT Promoter unmutated = complete unmethylation, which gives rise to the most aggressive of tumors.

IDH-1 negative (unmutated) + MGMT Promoter mutated OR vice versa (IDH-1 positive/mutated + MGMT Promoter unmutated) = sort of a half and half methylation, which gives rise to a lesser aggressive tumor

IDH-1 positive (mutated) + MGMT Promotor mutated, which gives rise to a completely methylated tumor, which in turn gives rise to the least aggressive tumor (apart from what other DNA bio-markers might do)

So, that's the genetics side of the story. The actual process side goes something like this...

Both of these genes (IDH-1 and MGMT Promoter) produce enzymes. When one or both of those genes are mutated, they produce flawed enzymes with an entirely new molecule, called 2-hydroxyglutarate. This molecule causes groups of atoms called methyl groups to latch onto the DNA strand (this is the part of the process called “methylation”).

So, along comes an alkylating chemo (like Temodar) which damages the tumor cells' DNA with the objective of killing the tumor cells. If the tumor's status is methylated (meaning that one or both of these genes are mutated), that damage cannot be repaired as easily because of the presence and interference of the methyl groups.

In the case where one or both of those genes are unmutated (giving the tumor an unmethylated status, whether complete or partial), then the absence of that methyl group producing molecule in the enzymes enables the tumor cells to rapidly repair and rebuild themselves, which is obviously not the preferred condition.

So, .....if a tumor is known to be IDH-1 positive, that tumor is methylated to some extent. If we also know something about the status of the MGMT Promoter gene, we can then understand if that methylation is complete or partial.