Ann: Expanded Heart Protection Discovery for Zantrene, page-284

If I may, JD, there really isn't enough data available to know which cancers patients will and won't benefit from Zantrene.

Is the synergy presumably due to FTO?

I have 100% confidence that the reason H929 was sensitive to Zantrene is because FTO was driving tumorigenesis in this cell line. There have been multiple other papers that have demonstrated FTO is fundamental to tumorigenesis in multiple myeloma cells (1-3). We also have a number of different papers that have shown Zantrene can kill cancer cells that overexpress FTO at low nM concentrations. I highly doubt there is another MoA for cancer killing.

And if this is the case, would a coformulation of Zan+Car as a synergistic drug mainly be relevant in Myeloma lines that are FTO sensitive?

That is not known at this point, but I would direct you towards this paper (4) and my post discussing it (5). In short, FTO knockdown in low-FTO cancer cells promoted growth, motility, and invasion. However, the FTO knockdown model sensitized the cancer cells to a WNT-inhibitor, which led to enhanced cancer cell killing. Based on this data, the Zan+Car may be relevant in Myeloma cell lines or patients that are not overexpressing FTO or relying on FTO to drive tumorigenesis.

Would this require a companion diagnostic for FTO level determination as well?

This can only be determined through clinical trials, I suspect.

Or would it be used mainly for cardioprotection and the synergy may/may not be important if a CDx isn't used?

My understanding is that could very well be the case. To quote Associate Professor Doan Ngo: "Zantrene was shown to salvage over 30% of carfilzomib-induced human heart cell from death. These results are genuinely remarkable, as with other clinically used cardioprotective drugs, we only observe a 10-15% protection from heart cell damage". This certainly gives me the impression that Zan would be useful, as there is a 100-200% improvement over current, approved cardioprotective agents. If the FTO inhibition of Zan is able to sensitize all MM patients to proteasome inhibitors, then an across the board approach will be used for improved anti-cancer efficacy and cardioprotection. Only time will tell.

1 https://www.nature.com/articles/s41388-021-01939-7
2 https://www.researchgate.net/publication/337248777

3 https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(21)00648-1
4 https://www.nature.com/articles/s43018-021-00223-7
5 https://hotcopper.com.au/threads/pillar-1-fto-new-thread.5839654/page-1202?post_id=54136583