Ann: Race Strategic Update March 2021, page-392

@RaceOncology

Can you comment as to whether the Andersson preclinical trial investigating the combination of bisantrene-clofarabine-fludarabine also included busulfan (a DNA alkylating agent)?

Based on the two articles below. AML cell lines resistant to busulfan upregulated anti-apoptopic genes like Bcl-2 and down-regulated pro-apoptopic genes like BNIP3. Inhibition of FTO was shown to decrease expression of Bcl-2 and increase expression of BNIP3, which would appose aspects of the AML resistance to busulfan. Importantly, busulfan has been shown to improve the therapeutic efficacy of clofarabine and fludarabine in AML cell lines. The last article is a fascinating read describing the role of epigentic modification in cancer cell resistance to DNA alkylating agents like busulfan.

Ultimately, this data suggests that there is another potential drug synergy for Bisantrene as a highly potent and selective FTO inhibitor.


AML resistant cell lines upregulate anti-apoptopic genes like Bcl-2 and down-regulate pro-apoptopic genes like BNIP3.
https://pubmed.ncbi.nlm.nih.gov/18339423/


It seems FTO inhibition decreases the anti-apoptopic Bcl-2 gene and increases the pro-apoptopic gene BNIP3.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437932/


The addition of busulfan to clofarabine and fludarabine significantly improves treatment efficacy.
https://www.researchgate.net/publication/239981019_Synergistic_Cytotoxicity_Of_Clofarabine_Fludarabine_And_Busulfan_Relevance_To_Myeloablative_Therapy


Potential for epigenetic modification to improve the efficacy of DNA alkylating agents like busulfan.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346159/


All IMO - DYOR.