What are the chances of Bisantrene actually reducing...

What are the chances of Bisantrene actually reducing Myelosuppression when combined with DOX..? Going to have a crack at this, but Mason (or any other Science boffins), please set me straight if i'm on the wrong track

Myelosuppression primarily affects the bone marrow's ability to produce blood cells and leads to Neutropenia (decrease in neutrophils or white/immune cells increasing risk of infection), Anemia (reduction in red blood cells (RBC) leading to fatigue, weakness, and shortness of breath) and lower Thrombocytopenia (reduction in platelets, increasing the risk of bleeding and bruising).

Based on the announcement on 30 June 2022 where mice were treated with Bisantrene, Doxorubicin or Doxorubicin + Bisantrene (at varying concentrations), we saw a trend of higher RBCs whenever Bisantrene was provided. Please look at the figure below. Interestingly, this was even seen with higher cytotoxic doses (18% BIS/DOX 1:1) and 36% BIS/DOX 2:1). Also, the article notes “no statistically significant change in blood and immune cells counts.”

This raises the question, does Bisantrene administered at lower doses (ie not chemotherapeutic doses of circa 200-300 mg/m2) improve blood cells counts, albeit not statistically significantly? Whilst I think we can all agree that Bisantrene is Myelosuppressive at high doses, does this data suggest it isn’t at lower doses…

I suggest we may beseeing the impact of raising m6A methylation. I failed to find any FTO specificstudies that look at reduced FTO levels and the impact on blood and immune cellcounts. However, I did come across a quality paper that looked at METTL3 (writer)knockdown and the impact on blood cell counts. The below shows that METTL3 knockdownsignificantly reduces cells counts. This clearly shows the importance of m6Amethylation on blood cell counts. Based on this study and the Race study, it’s quitepossibly the case that higher m6A methylation increases cell counts.

https://doi.org/10.1016/j.celrep.2019.07.032

The science does get complicated in this area and given I don’t have a science background, I’ll resist going any further.

However, acccording to Chatgbt “higher m6A methylation can lead to increased red blood cell production by enhancing the stability and translation of mRNAs involved in erythropoiesis, promoting hepatopoietic stem cells (HSC) differentiation into the erythroid lineage, and regulating gene expression critical for red blood cell maturation.”

Why is this important?

As we approach the phase trial, I’ve been considering the major dose-limiting toxicities we’re likely to see when we carry out the dose escalation. If we can provide higher doses due to limited DLT’s then we will obviously be better treating the cancer. The most serious dose limiting toxicity of anthracyclines (as ranked by physician concern) is Cardiotoxicity, however Myelosuppression is the most common dose-limiting toxicity.

Lyman GH. Chemotherapy doseintensity and quality cancer care. Oncology (Williston Park). 2006 Dec;20(14Suppl 9):16-25. PMID: 17370925.