I thought a dedicated thread for CPACS was required.
I think I have discovered a reason outside m6A levels for the lead-in dose of Bisantrene 7-days prior to the combination.
Below is a 1984 abstract investigating the immunomodulating effects of Bisantrene. The paper found that providing 6 and 12 mg/kg Bisantrene 5 or 15 days prior to tumor implantation produced greater increases in life span and numbers of long-term survivors than a standardised therapeutic fashion of 100 mg/kg on day +1. Durr suggests this is through macrophage activation, where M1 macrophage activity has been consistently shown to demonstrate anti-tumor as well as anti-bacterial effects.
6 mg/kg in mice converts to 18 mg/m² in humans
12 mg/kg in mice converts to 36 mg/m² in humans
100 mg/kg in mice converts to 300 mg/m² in humans
Below is work completed by Wang et al 1986 investigating bisantrene-activated macrophages in a number of tumor xenograft models, where bisatrene-activated macrophages significantly improved survival in murine models. The figures depict bisantrene-activated macrophages given as a single dose at day 0 (top left) and day 4 (top right), and multiple doses on days 7 and 14 (bottom left) and days 3, 9, and 14 (bottom right).
More work by Wang in 1984 indicates that a 50 mg/kg dose of Bisantrene in mice is the optimal macrophage-stimulating dose, which equates to approximately 150 mg/m2 in humans.
He further demonstrated that a 100 mg/kg (300 mg/m2) dose activated >80% cytostatic macrophages for 2-weeks, and significantly for up to 4-weeks.
FTO inhibition/knockdown has been shown to ablate M1 macrophage activation, which means M1 macrophage activation is happening independent of FTO inhibtion. With the inclusion of M1 macrophage activation, Bisantrene has at least 5 therapeutic targets in vivo including FTO, DNA, telomerase, cardioprotection MoA, and now M1 macrophage activation. This concept may seem strange today where compounds are highly selective, but it was very common for the era in which Bisantrene was produced (e.g. doxorubicin). Because chemotherapy was typically a single agent treatment, compounds were ranked based on the broadness of their activity. The extremely interesting thing for me is how 6 mg/kg of Bisantrene in mice was sufficient to significantly increase M1 macrophage activity, which would imply a very low concentration requirement for the activation of this system.
Something which I only became aware of because of
@Boffin99 excellent research, RAC have included Abraxane (nab-
paclitaxel) as an example of a reformulation. Paclitaxel is primarily a microtubule inhibitor, but has been shown to have immunomodulatory effects that reduce tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner. Coincidence? I think not!
If this is something that translates to humans, it explains Bisantrene being used 7-days before the Bis+Dox combination in the upcoming P1a/b trial. They are probably going to measure macrophage activity/polarization as well as m6A levels. There really is so much to learn about this drug!
(20min delay)