Dr Chen - FTO paper 2.0, page-26

Lol. If you are down an RAC rabbit hole, it won't take you long until you find me and likely many others. Your post sparked some research for me, which has produced some very interesting results. I must admit that I am skeptical and cautious of the fasting protocol as an adjunct to SoC drugs hypothesis. This is largely based on my experience with fasting. I do not know if you have done a fasting protocol before, but if you have, then you will know that they can be extremely difficult. I have done a couple of 24-hour fasts before and have had mixed experiences from easy to struggle-town. I imagine that if I was suffering from cancer and undergoing intensive chemotherapy, I may not have the motivation or strength to maintain such a thing. Hence, I suspect that compliance would be a major issue to overcome, without delving into the risks of malnutrition and complications associated with that.

Anyway, after looking into the area, it turns out that there is some clinical data (1). This was a phase 2 trial including women with stage II/III BC comparing those following a regular diet and a fasting mimicking diet (FMD), a super-low calorie diet including bone broths, vegetables, and soups. Intriugingly, the FMD group performed much better than the regular diet group with no additional toxicities. It's quite fascintating that the fasting protocol demonstrated far greater 90-100% tumor-cell losses than the regular diet group. If the study population was expanded into a phase III trial (it was stopped due to funding), I imagine the P values would become much stronger.



As I mentioned above and expected, compliance to the fasting protocol was challenging for some patients with 81.5%, >50%, 33.8%, and 20% completed 1, 2 and 3, 4, and 5 cycles of chemotherapy, respectively. Interesting that the major complaint was the dislike of distinct compenents of the diet. I understand that chemotherapy can alter the taste buds and make things taste like ash. Maybe a complete abstinence from food would be better?



This then prompted me to determine whether an alteration of FTO function could have had a hand in this. Turns out the FTO gene activity is nutritionally regulated with a high fat diet, fasting, and glucose and protein ingestion (2-6).

It seems that the case for fasting protocols as an adjuvant to SoC anti-cancer therapies is building. However, I think they need extremely strong clinical data to motivate patients enough to overcome the issues with compliance. I must say that I immediately think preventative over curative and wonder about implementing a fasting protocol of my own - just for fun.

There also appears to be data available linking protein, carbohydrate, and fat intake to the expression levels of FTO, as well as mouse model data demonstrating that fasting decreases FTO expression. Could the fasting protocol have modulated the expression of FTO in these breast cancer patients? And could that modification of demethylase activity have synergised with the SoC therapies? If only that Nature article (1) had measured FTO expression levels and/or methylation/demethylation.

1 https://www.nature.com/articles/s41467-020-16138-3.pdf
2 https://www.nature.com/articles/nutd201115
3 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008771
4 https://pubmed.ncbi.nlm.nih.gov/17991826/
5 https://www.tandfonline.com/doi/full/10.1080/21623945.2019.1693745
6 https://academic.oup.com/cdn/article/4/Supplement_2/1706/5844257