Ann: Expanded Heart Protection Discovery for Zantrene, page-326

Great find, @wombat777

I'm just going to break this down into each individual part, so investors can hopefully begin to appreciate the consistency that we are seeing between treatments and highlight the central role FTO is playing in cancer.

Clearly, first of all, FTO is highly expressed in multiple myeloma (MM) cells - this means that relative to a normal cell, a MM cell has a lot more FTO, which leads to greater levels of demethylation (removal of a methyl group - de (removal) methylation (indicating a methyl group and an action). Importantly, the cell/s used in this study are different to the H929 cells used in the carfilzomib study, highlighting the importance of FTO across a range of different MM cells.



It's important to note going forward that theoretically an FTO knockdown (FTO KD) model is exactly the same as 100% pharmacological inhibition of FTO. Both models prevent demethylation from occuring, so m6A content increases intracellularly. FTO KD enhanced the effect of Bort on cell apoptosis (cell suicide), proliferation (spreading and multiplying), and G0/G1 cycle arrest. What I found interesting was that when FTO KD was used in Bort treated cells, it improved apoptosis by 4 fold relative to Bort or FTO KD used on is own.



The gene that was being influenced is called SOD2. Basically, when Bort was being used on MM cells, it upregulated FTO (leading to increased demethylation [removal of a methyl group]) leading to decreased SOD2 expression, which enhanced the MM cancer features and induced Bort resistance. An FTO KD model abolished this downregulation of SOD2 which suppressed MM cancer features and improved Bort sensitivity.

Lastly, when used in mice, Bort and FTO KD used in combination demonstrated a significant reduction in tumor volume compared to either FTO KD or Bort used singularly. Highlighting the benefit of combining Bort (proteasome inhibitor) treatment in conjunction with an FTO KD (or pharmacological inhibition) model.



This is not the first time that we have seen data like this. The consistency at which information like this is coming out for multiple different anti-cancer therapy synergies as well as different cancers being driven by FTO is overwhelming.

Not only do we have the best and first FTO inhibitor, but we have the ONLY FTO inhibitor that confers cardioprotection.