Oh, and then there is also this study released in January 2024 -
@Teeth I don't know if you have shared this yet, but it's extremely good
I'm going to break this work down, because it relates so closely to the Phase II combination trial with Aracytine (Ara-C) in relapsed/refractory children where Bisantrene and Ara-C achieved a 46% CR.
FTO is highly expressed in t(8;21) AML and positively correlated with AML1-ETOThis research found FTO was upregulated in t(8;21) AML, a subtype of AML, when compared to healthy individuals. Among the patients studied, some had a tougher form of this cancer that did not respond well to initial treatments; these patients had even higher activity of FTO. Additionally, it was noted that a significant portion of t(8;21) AML patients have another genetic change in a gene called c-KIT, which usually means a worse outlook for the patient.The researchers observed that for patients without the c-KIT mutation, when they achieved full remission (meaning their cancer signs had disappeared), the activity of the FTO gene went down. They divided the patients into two groups based on the levels of FTO activity: high and low. It turned out that patients with high levels of FTO had a lower overall survival rate compared to those with low levels. This suggests that high FTO activity is associated with a worse prognosis in this type of leukemia.
FTO is crucial for the sensitivity of t(8;21) AML cells to Ara‑CThe study found that FTO expression was significantly higher in patients resistant to Ara-C when compared to those more sensitive. Using human derived cell lines that were resistant to chemotherapy, FTO overexpression exacerbated resistance to Ara-C while FTO knockdown (inhibition) restored sensitivity to Ara-C. Pre-exposing the chemoresistant cell lines to the FTO inhibitor FB23-2 and following with Ara-C treatment demonstrated notably lower IC50 values required for efficacy and apoptosis. Combination therapy also had a significant impact on proliferation.
F The external view of nude mice bearing SKNO-1 cell xenografts (n = 6 for each group) treatedwith DMSO, Ara-C, FB23-2, or a combination of Ara-C and FB23-2.
G, H The growth curve of tumor volume (G) and the final tumor weight (H)for each group as indicated in
F
I think that this is as good as it is going to get for confirmation that Zantrene was functioning directly as an FTO inhibitor with synergised with Ara-C in this Phase II paediatric trial for AML. This is the following from that paper "Induction therapy consisted of bisantrene, 250 mg/m2/d, infused in I hour without any pretreatment by acentral venous line from day 1 to day 5 with HD Ara-C,IOOO mg/m2, infused in 2 hours twice a day from day I today 5". The worlds most potent inhibitor of the FTO protein was given side-by-side with Aracytine (Ara-C) in children with refractory and relapsed disease, where FTO is identified and implicated as the primary cause for chemotherapy resistance. I believe the only plausible explannation for efficacy is Bisantrene is inhibiting FTO sensitizing resistant AML cells to Ara-C activity. To be able to put these pieces together from historic and recent research marks a significant milestone in a long list of derisking events for me. Most investors in biotechnology are fearful of clinical trials, as the binary outcome of good vs bad can cost people big $. As well as clear clinical efficacy in a very unwell patient group, there are no reported signs of cardiotoxicity.
