Pillar 1 - FTO (new thread), page-558

FTO and metabolic disorders

Epigenetic modifications have been demonstrated to be closely related to the onset and development of metabolic abnormalities and cardiovascular diseases. While doing this research, I have realised that the evidence currently available does not provide all the answers we need to accurately value a potent FTO inhibitor like bisantrene. However, the associations that have been found between FTO and metabolic diseases almost doubles the potential yearly drug market value that a potent FTO inhibitor could access a percentage of in the current healthcare ecosystem. Hence, emerging evidence suggests that epigenetic modification and/or modulation could be the future of disease therapy.

Type 2 Diabetes (T2DM), obesity, and non alcoholic fatty liver disease (NAFLD)

FTO overexpression has been linked to T2DM, obesity, and NAFLD progression and pathogenesis (the manner of development of disease) (1). The mechanism shown below indicates that FTO increases expression of FOXO1, which has a downstream effect on T2DM and NAFLD. Importantly, targeting FTO may then influence a number of different disease outcomes and states. In the table below, follow the yellow arrows that lead away from FTO into FOXO1 and RUNX1T1, indicating that FTO influences the expression of these proteins, which in turn influences the pathogenesis/progression of the diseases/states linked to each.

Obesity is a significant risk factor for T2DM and NAFLD (2). Those who have T2DM have increased risk of NAFLD and vice versa (3). At the center of these diseases and states is epigenetic modification and more specifically FTO and FOXO1.

NAFLD - An unmet clinical need

Currently, there are no clinically approved medications available for NAFLD or the more serious downstream progression of NAFLD called non alcoholic steatohepatitis (NASH). Hepatic (liver) FTO was found to be overexpressed in NAFLD as well as NASH. Currently, a T2DM drug called pioglitazone improves NASH in people who don’t have diabetes.

Metformin & FTO

Metformin is the drug of choice for type 2 diabetes which accounted for USD ~2.2B in 2018. Research reports that FTO overexpression counteracts the activity of metformin, which inhibits gluconeogenesis and adipogenesis (4). Also, metformin was recently shown to induce DNA methylation, which may counteract upregulation of FTO expression in breast and prostate cancer. This evidence suggests that a potent FTO inhibitor may be used in conjunction with metformin, and therefore also identifies another potential drug synergy for Bisantrene.

Polycystic ovarian syndrome (PCOS)

Digging deeper into metabolic conditions that may be associated with FTO led me to find that the FTO rs9939609 variation was significantly associated with PCOS (5). Currently, there are no clinically approved medications available for PCOS and instead, drugs used for regulating glucose and blood lipids are used to optimize patient health.

Atherosclerosis

Atherosclerosis is the most prevalent disease threatening vascular health and is characterised by lipid deposition and fibrous cap formation in blood vessels (6,7). Overexpression of FOXO1 binds to the ApoC3 promoter leading to an increase in ApoC3 expression, which leads to dysregulation of fat metabolism and influences the pathogenesis of atherosclerosis and hypertriglyceridemia (high levels of fat in the blood). A study demonstrated that loss of endothelial FTO prevented obesity-induced vascular dysfunction in mice. Loss of FTO would lead to a reduction in FOXO1 expression, which may have then influenced ApoC3 expression. Notably, more research is needed to elucidate the role of FTO in atherosclerosis.

Hypertension

A meta-analysis comprising 57,464 hypertensive patients and 41,256 controls demonstrated that the FTO variant was related to hypertension in both European and Asian populations (8). A study in mice found that loss of endothelial FTO prevented the development of obesity-induced hypertension by preserving myogenic tone in resistance arteries (9). However, more in-depth research on functional analysis is needed to understand the mechanism by which FTO may influence the risk of hypertension.

FOXO1 - A common genetic factor

Dysregulation of FOX01 has been linked with several metabolic conditions, including obesity, T2DM, NAFLD (& NASH), and atherosclerosis (accumulation of fat in blood vessels) as well as wound healing and cancer (10). Because of this, there have been many efforts to design small-molecule compounds to treat metabolic disorders - namely, FOXO1 inhibitors. FTO protein demethylation enhances the expression of FOXO1 (11). Research has shown that selective inhibition of FTO decreases the amount of FOXO1 protein in vivo (living things). With an IC50 value of 3.5 uM, the selective, small-molecule FTO inhibitor entacapone decreased FOXO1 expression, thus suppressing gluconeogenesis (creation of new glucose molecules) and increasing thermogenesis (heat production) in mouse models. The article states that “selectively suppressing FoxO1 activity through the inhibition of FTO by entacapone provides the possibility to treat type II diabetes and obesity.”

By comparison, Bisantrene was found to inhibit FTO in AML cell lines with an IC50 value of 22 - 176 nM, which is approximately 20-fold more potent than entacapone.

Alzheimer’s Disease (AD)

Importantly, obesity and type 2 diabetes are risk factors for AD, which are also both related to FTO. Research found that FTO knockout reduced the cognitive defects in triple-transgenic AD mice and states their findings demonstrate that FTO is critically involved in insulin defects-related AD (12).

A table summary of the role of FTO in disease with global prevalence/incidence and drug market figures

Importantly, since the recognition of FTO as a potential therapeutic target in metabolic disorders, it lifts the total potential yearly drug market value from USD $145B for just cancer in ~2019 to USD $288B - that is an increase in addressable drug market value of USD $143B (+98.6%). Clearly, a therapeutic agent aimed at inhibiting FTO would target a percentage of the yearly drug market value, which has doubled in potential for 2019. By 2026, a potent FTO inhibitor able to modulate epigenetic modification and influence disease outcomes may be able to access over a half-a-trillion dollar revenue potential. Notably, the frequency of data relating to epigenetic modification and disease is increasing and as new data comes to light that clearly identifies the role of FTO inhibition in health and disease, we may more clearly understand the potential of a highly potent and selective FTO inhibitor.

Conclusion

While strong associations have been made between FTO and cancer, this data highlights the therapeutic potential of targeting epigenetic modulators with highly potent and selective pharmacological substances in certain metabolic conditions. Also, as observed with anti-PD-1 and TKI-inhibitor cancer therapies, it appears that pharmacological inhibition of FTO could synergise with drugs designed for metabolic disorders, highlighting the versatility and expansion of potential. With the addition of diseases that are linked with FTO expression, access to yearly drug market revenue by 2026 increases from USD $311B for just cancer to USD $577B (+85.5%). To my best available knowledge, bisantrene, a highly selective and potent FTO inhibitor, could become a new class of drug that modulates the genetic makeup of a person to improve health and reduce the impact of disease. More in-depth research is required before we can truly understand the implications of epigenetic modulation on human health as well as the potential and efficacy of drug treatment synergies available.

1https://www.sciencedirect.com/science/article/pii/S2352304220300945

2https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575093/

3https://clindiabetesendo.biomedcentral.com/articles/10.1186/s40842-020-00097-1

4https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-015-0746-z

5https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401934/

6https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016779/pdf/cells-09-00184.pdf

7https://www.sciencedirect.com/science/article/pii/S2352304220300945

8https://www.sciencedirect.com/science/article/pii/S2352304220300945

9https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.315531

10https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016779/pdf/cells-09-00184.pdf

11https://stm.sciencemag.org/content/11/488/eaau7116/tab-pdf

12https://www.sciencedirect.com/science/article/pii/S0006291X18304571?via%3Dihub