@Mason14 and
@Davisite, thanks for all the recent posts, I'm sure I'm not the only one who has found all of this extremely interesting and educational.
Sorry if my questions are pedantic or based on misunderstanding something, but I wanted to try and reconcile a few things that have come up recently in my mind based on the information that has been presented...
1) When you (
@Mason14) say "
FTO inhibition/knockdown has been shown to synergize with doxorubicin and other cardiotoxic drugs to more effectively kill HCMs (Figure 1)." (and this applies to pretty much all the other statements/links between FTO and cancer that you make), does it strictly mean FTO inhibition/knockdown or does it more generally mean increased m6A levels, whether it would be achieved by FTO inhibition or some other mechanism?
2) I ask this because yesterday there was a discussion based on what @Davisite said about Race not specifically measuring FTO activity but instead the downstream result of increased m6A levels. For example, if there was another way of increasing m6A levels, not by FTO knockdown but perhaps if there was a drug that behaved the opposite of Storms drug and increased METTL3 expression but didn't change FTO and thereby increased m6A levels (not that I'm stating such an drug/MoA is possible or feasible), would this have the same anti-cancer effect as increasing m6A levels by FTO knockdown?
3) Following on from that, @Davisite said yesterday that due to the complexity of the m6A system, for example it's possible that the body may compensate against an FTO inhibition/knockdown by reducing METTL3 and thereby maintain or even reduce m6A levels after treatment with Bisantrene. In this instance, if the anti-cancer effect was linked specifically to FTO inhibition (i.e. it's having some other effect in addition to changing m6A levels), we would still expect to see Bisantrene to provide improved anti-cancer activity, but if it is actually the downstream effect of the increase in m6A levels, we would expect less (or no) anti-cancer activity. The answer here may be that we do not know, but in this case should we measure both FTO inhibition and m6A levels? Or maybe it's not even possible to measure FTO inhibition?
4) Following on from 3), I expect we will see an anti-cancer effect based on all of the prior history of Bisantrene, but if that does not correspond with an increase in m6A levels, what would be the impact of that? Will it be possible to go back to the samples and then try to measure FTO inhibition specifically, or look for other changes in the before and after samples, to try and identify the exact MoA? I understand this may be a moot point due to information that Race has already gathered but has not released due to IP protection or other reasons.
5) How/where do we measure m6A levels before and after treatment with Bisantrene? Is it in a biopsy of the tumour cells, or some other non-cancerous tissue cells, or from cells in a blood sample, or even from external cells e.g. skin cells? Is Bisantrene distributed throughout all cells in the body equally (I remember reading somewhere it is more concentrated in the heart, but I assume we will not be taking a heart biopsy!) ? Will the effect of Bisantrene on FTO inhibition/m6A levels be the same in all cells no matter where we measure it? Do all types of cells in the body even function identically when it comes to FTO and m6A levels or are there differences depending on where those cells are or their function in the body?
I hope these questions make sense. Thank you in advance for your any further information you can provide.
(20min delay)