Industry news, page-1684

By inhibiting FTO (a protein that demethylates), you prevent demethylation - which in turn increases methylation rates and as a result m6A levels.

FTO up = m6a down
FTO down = m6A up
FTO inhibited = m6a up

People are sleeping on the Sheba 2 data.

FTO overexpression (decreased m6A) promotes gemcitabine, Ara-C, and 5-FU resistance. FTO inhibition/knockdown (increased m6A) resensitizes AML cells to Ara-C, pancreatic cancer cells to gemcitabine, and colorectal cancer cells to 5-FU making the therapies work again. These are all antimetabolites like clofarabine and fludarabine.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10807068
https://pubmed.ncbi.nlm.nih.gov/37914721/
https://pubmed.ncbi.nlm.nih.gov/36307991/
https://www.nature.com/articles/s41420-024-02020-4
https://www.sciencedirect.com/science/article/abs/pii/S0013935123025872

Sheba 2 patients had an average of 4 (3-9) lines of therapy and were all resistant to their last line of therapy, yet 40% (5CR / 1PR) responded to the combination.

Through the inhibition of FTO and thereby increasing m6A levels, Bisantrene was able to (re?)sensitize refractory AML patients to the cytotoxicity of clofarabine and fludarabine.

This is the second time it has happened.

Originally, Bisantrene re-senstized children who were all refractory to Ara-C achieving a 57% CR rate in combination with Ara-C. There are two papers clearly supporting the role of FTO overexpression in Ara-C resistance in AML and FTO inhibition/knockdown in resensitizing AML to treatment of Ara-C.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10807068
https://www.sciencedirect.com/science/article/abs/pii/S0013935123025872