Pillar 1 - FTO (new thread), page-369

While creating the following PDF documents, I have noticed that there has been a lot of information that has come out since the start of the year. While I have commented on some of this information, there have been many papers released to the public that I assume have been missed by all of us, yet are important to understand and be aware of. My point is that the FTO space is not rigid or fixed, it is dynamic, changing, and growing, with new discoveries each month that change the way we look at cancer and its therapies. My aim is to bring enough knowledge to you so that you understand and appreciate the opportunity that we have before us and do not settle for what it is not worth.

Introduction

The following image is a synthesis of all the important information I have collected to date regarding FTO and cancer, however, after completing this research, I have realised that it is out of date and needs some tidying up.

Notably, there are inherent difficulties with valuing this FTO opportunity, which is largely because an FTO inhibitor has never been purchased before. I do not know if there has been a cancer therapy discovered before that has the potential to address as much of the market as Bisantrene. As you will see below, there are new discoveries being made weekly, and while those discoveries may not be directly looking at the effect of on FTO inhibitor on tumorigenesis, they shed light on the mechanistic pathway of m6A methylation/demethylation and its role in cancer progression. In an effort to quantify the FTO value of Bisantrene, I have used the buyout scenarios of Magrolimab and Trodelvy, since these drugs have differing development stages, multi-tumor efficacy, and potential drug synergy like bisantrene. I estimate that based on peers, the FTO opportunity could be between $30.6 and $131.2 per share, however, I realise that true value for the FTO opportunity may lie within or outside of these share price estimates.

The following information has been collected since the start of the year and includes some feature articles that aid in providing additional context.

Potential drug synergies

Firstly, and arguably the most exciting, are papers that suggest FTO inhibition could improve the efficacy of proton pump inhibitors, androgen receptor binding inhibitors, and phosphoinositide 3‐kinase (PI3K)‐targeted therapies. Based on the research that I have done, that brings the total potential synergies to eight (Table 1). As identified by Wombat, the different cancer treatments total USD >$100B in revenue each year.

Table 1: List of potential cancer synergies

PD-1 Inhibitors

https://pubmed.ncbi.nlm.nih.gov/31239444/

Cisplatin

https://pubmed.ncbi.nlm.nih.gov/29315835/

TK inhibitors

https://pubmed.ncbi.nlm.nih.gov/30297871/

PARP inhibitors

https://pubmed.ncbi.nlm.nih.gov/31239444/

Radiotherapy

https://pubmed.ncbi.nlm.nih.gov/29315835/

Proton pump inhibitors

https://portlandpress.com/bioscirep/article/41/1/BSR20200842/227460/Omeprazole-improves-chemosensitivity-of-gastric

Androgen Receptor Binding Inhibitors

https://www.biorxiv.org/content/10.1101/2021.01.12.426354v1.full.pdf

PI3K therapy

https://onlinelibrary.wiley.com/doi/full/10.1111/jcmm.16291

Importantly, the papers investigating the new potential synergies were not looking directly at the relationship between FTO inhibition and their drugs effectiveness. Some interpretation and extrapolation of the data is required. For the AR binding inhibitor, the study found that downregulation of METTL3 rendered cells resistant to AR inhibitors (1). Thus, if downregulation of METTL3 and FTO overexpression create similar abundance of mRNA, then FTO inhibition could reduce AR binding inhibitor resistance in pancreatic cancer cells that overexpress FTO. Omeprazole, a proton pump inhibitor, was shown to downregulate FTO, which improved the antitumor efficiency of chemotherapeutic drugs on GC cells (2). If further FTO inhibition was achieved via a potent FTO inhibitor, the efficacy may be further improved. Lastly, the PI3K inhibitor, GSK3B, suppressed tumor progression by reducing FTO expression in colorectal cancer cells (3). Again, could further FTO inhibition in high-expressing colorectal cancer cells lead to improved suppression of tumor progression.

https://www.biorxiv.org/content/10.1101/2021.01.12.426354v1.full.pdf

https://portlandpress.com/bioscirep/article/41/1/BSR20200842/227460/Omeprazole-improves-chemosensitivity-of-gastric

https://onlinelibrary.wiley.com/doi/full/10.1111/jcmm.16291

Small molecule FTO inhibitors

There have been three publications that have tried to develop small molecule FTO inhibitors (1-3). I have discussed one of these already (1), FTO-04, however there are two others that I had missed originally; namely, SYG00001666 (2) and compounds 2 and 3 (3). Like FTO-04, all three of these newly discovered/synthesised compounds have IC50 values in the uM range - which is quite high for a drug. Ideally, drugs should be exhibiting an effect in the nM range (1000 times smaller concentration). These studies highlight the specificity and efficacy of bisantrene at inhibiting the FTO protein with extremely low doses between 22nM and 175nM.

https://pubs.acs.org/doi/10.1021/acschembio.0c00841

https://www.sygnaturediscovery.com/wp-content/uploads/2019/08/FTO-Poster.pdf

https://www.biorxiv.org/content/biorxiv/early/2021/02/24/2021.02.23.432419.full.pdf

Association between FTO and cancer

While I have commented on one paper that linked FTO expression to bladder cancer (1), there was another paper that confirmed these findings released in January 2021 (2). The study found that FTO decreased m6A levels in PYCR1 cells which promoted bladder cancer initiation and progression. Also, the FTO protein was negatively associated with overall survival in bladder cancer patients. Importantly, prior to January 2021, it was thought that FTO was down-regulated in bladder cancer (3). Taken together, these articles highlight the relationship between FTO overexpression and bladder cancer, while also providing reasonable evidence to encourage pharmaceutical interventions that may attenuate rising FTO concentrations to improve bladder cancer patient outcomes.

In January and February 2021, there were two reviews for the role of FTO in breast cancer and gastrointestinal cancer (GIC) (4,5). The role FTO overexpression plays in breast cancer, describing how m6A demethylases affects breast cancer cells via different molecules and signaling pathways, how m6a demethylase exhibits abnormal expression in breast cancer tissues and is related to certain breast cancer subtypes, and relating breast cancer prognosis to the atypical expression of m6A demethylase (4). In GIC, the paper explored the role of FTO in RNA methyladenosine modifications in gene expression and the resulting tumorigenesis, cancer progression, and drug resistance, highlighting the potential therapeutic regimens for GICs (5). More research has discussed FTO overexpression in multiple different cancer types with multiple genetic targets which causes changes to behaviour of tumor cells including cell proliferation, migration, chemo-radiotherapy resistance, metastasis, colony formation, and survival (6). FTO was further linked with myeloblast proliferation, Gefitinib (tyrosine kinase inhibitor) sensitivity and efficacy, and gastric cancer (7-9). Papers that were not as specifically directed towards FTO had identified and linked the m6A mechanism to chemoresistance of cisplatin in ovarian cancer (10) as well as downregulation of the other m6A demethylase linked to uveal melanoma (11).

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ctm2.310

https://www.aging-us.com/article/202359/pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751723/pdf/ott-13-12845.pdf

https://www.frontiersin.org/articles/10.3389/fcell.2020.615071/full

https://www.frontiersin.org/articles/10.3389/fonc.2020.586789/full

https://www.frontiersin.org/articles/10.3389/fonc.2020.623634/full

https://www.sciencedirect.com/science/article/abs/pii/S0014482721000550

https://mcr.aacrjournals.org/content/early/2021/02/09/1541-7786.MCR-20-0541

https://www.researchgate.net/publication/342883862_HDAC3-dependent_transcriptional_repression_of_FOXA2_regulates_FTOm6AMYC_signaling_to_contribute_to_the_development_of_gastric_cancer

https://www.sciencedirect.com/science/article/abs/pii/S0167488920302366?via%3Dihub

https://www.aging-us.com/article/202371/text

m6A methylation/demethylation mechanism

With regards to tumorigenesis, the m6A methylation/demethylation mechanism is attracting a lot of attention. If you are not familiar with the terms ‘readers’, ‘writers’, and ‘erasers’, then I encourage you to do some googling. There have been studies that suggest the downregulation of METTL3 leads to cancer growth and metastasis as well as AR binding inhibitor resistance (1,2). What is important to take away from this is that due to the downregulation of METTL3, there would be an accumulation of demethylated mRNA, which is similar to the outcome of FTO overexpression. Given the large body of evidence that supports the relationship between FTO overexpression and tumorigenesis, I believe it is reasonable to suggest that FTO overexpression may lead to similar outcomes identified in this study (Figure 1).

Figure 1: A comparison of downregulation of METTL3 and FTO overexpression on mRNA levels.

https://www.unboundmedicine.com/medline/citation/33484966/METTL3_restrains_papillary_thyroid_cancer_progression_via_m6A/c-Rel/IL-8_mediated_neutrophils_infiltration

https://www.biorxiv.org/content/10.1101/2021.01.12.426354v1.full.pdf

Mutant-RAS Cancer and FTO

This paper explored the relationship between m6A methylation and initiation pausing (1). Importantly, mutant-RAS type cancers are present in 26 different cancer types and studies show that 16% of those cancers will have mutated RAS components (2). Reduced m6A methylation (FTO overexpression) led to relaxed initiation pausing, which promoted malignant transformation and tumor growth. Also, the study found that initiation pausing could be restored by inhibiting m6A demethylases, which suppresses RAS-mediated oncogenic translation and subsequent tumorigenesis. This study highlights not only a mechanistic pathway of FTO in tumorigenesis, but a key therapeutic opportunity for a potent FTO inhibitor.

https://advances.sciencemag.org/content/7/8/eabd6927

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354961/

Conclusion

In summary, the understanding of the relationship between FTO and cancer is an ever growing body of research. Namely, FTO overexpression has now been clearly linked with bladder cancer and mutant-RAC cancer types, chemoresistance, as well as potential new cancer drug synergies. The m6A mechanism is a focus for research with new discoveries being made. While multiple papers are searching for small molecule inhibitors of FTO, they appear to lack certain criteria that would make them effective in the clinic. Thus, highlighting the therapeutic role a potent FTO inhibitor, like BIsantrene, could play in the cancer therapy landscape.