The availability of highly technical data for free on the internet astounds me. The following is too good not to share, but let's briefly and simply explain m6A epitranscriptomics.
Imagine a human cell as a bustling city. In this city, FTO acts like the power plant, supplying energy to various essential services:
Hospitals: Representing cell repair mechanisms.
Painters: Symbolizing immune defenses.
Maintenance crews: Preventing cell death.
Construction teams: Promoting growth.
Transport and logistics networks: Facilitating invasion and metastasis.
The power plant, FTO, removes methyl groups from m6A (a specific type of marker) to energize these services. The more methyl groups FTO removes, the more energy these city functions receive.
In cancer, the power plant becomes overactive, removing too many methyl groups. This causes the city's services to go into overdrive, leading to uncontrolled growth and spread of cancer cells. For example, painters are able to hide the city from the attack from the immune system, construction teams build at unbelievable pace, and transport networks stretch further and further into neighbouring territories.
Bisantrene steps in like a regulator, cutting the excessive power supply from the power plant. This prevents the city's functions from being over-energized. As a result, the methyl groups can reattach to form m6A, restoring balance to the cell.
With higher levels of m6A, the cell operates in a more controlled, natural way, keeping growth and other functions in check.
Hopefully, that is an analogy that will help you understand the following points. The TNMplot database collates roughly 60,000 human samples from 4 major genomic databases. The information and service is free to use, and contains an enormous web of data as well as functions to understand key trends.
https://tnmplot.com/analysis/Naturally, I generated some figures of my own, and the information contained within highlight consistently how important a prognostic and therapeutic marker FTO is in cancer.
As discussed above, FTO drives
demethylation (the removal of methyl groups) which decreases the amount of m6A. The following figure captures the FTO gene expression in 22 different cancer types. FTO gene expression is significantly upregulated relative to normal tissues in 18 of 22 (82%) cancerous tissues, with no significant difference in the remaining 18% (4 / 22). There are no cancers where FTO is significantly downregulated relative to normal tissue. Simply put, m6A levels are frequently lower in cancerous tissues relative to normal tissues.
METTL3 and METTL14 are writers, and their role is to methylate m6A, which increases the amount of m6A. They do the opposite job to FTO.
The following figure captures the METTL14 gene expression in 22 different cancer types. METTL14 gene expression is significantly upregulated relative to normal tissues in 5 of 22 (23%), significantly
downregulated in 7 of 22 (
32%), and not signfiicantly different in 10 of 22 (45%) cancerous tissues relative to normal.
The following figure captures the METTL3 gene expression in 22 different cancer types. METTL3 gene expression is significantly upregulated relative to normal tissues in 1 of 22 (4%), significantly
downregulated in 18 of 22 (
82%), and not signfiicantly different in 3 of 22 (14%) cancerous tissues relative to normal.
This data highlights to a high degree of consistency that relative to normal tissue, cancerous tissue has consistently lower m6A levels. This is evidenced by the high number of cancerous tissues with upregulated FTO gene expression in combination with the high number of cancerous tissues with significantly downregulated or non-significantly different METTL3 and/or METTL14 gene expression.
FTO controls the expression of thousands of genes and proteins, and has never been a therapeutic target in cancer before. There are no clinical or commercial competitors in the space, and current preclinical compounds are not demonstrating the potency typical of precision agents. It is not yet known what the future holds for FTO inhibitors, but Bisantrene is the most-potent FTO inhibitor with an entire database of information supporting its safe use in humans as well as strong clinical efficacy. To add cardioprotection into the mix makes this an extremely exciting opportunity.
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