Cardioprotection thread, page-609

Yeah, there is a risk of that, although...

1. Precision Oncology

Bisantrene's primary anti-cancer MoA (FTO inhibition) either alone or in combination with other drugs technically falls into the category of precision oncology - selecting patients based on their sensitivity to Bisantrene or the combination. Patients who's cancers are unresponsive to treatment will therefore be unlikely candidates. This is not being done in the P1a/b CPACS trial, but we do have the Oncolines data that has shown Bisantrene is sensitive in 79% of cell lines, and synergises with Doxorubicin and Decitabine in 86% and 92% of cell lines, respectively.





2. Oncolines Track Record

The Oncolines cell lines have generated some outstanding data that has correlated with FDA approvals for multiple drugs and synergies cancer targets. Two examples that I can use are: 1) where the Oncolines cancer cell lines demonstrated a high degree of agreement between efficacy in cell line mutations and FDA approved cancer mutation targets for a list of 34 different approved kinase inhibitors; and 2) identifying "the combination of dabrafenib and trametinib is specifically targeted to oncogenic BRAF-signaling" 7-years before "the FDA approves dabrafenib and trametinib for the treatment of people with nearly any type of advanced solid tumor that has a specific mutation in a gene called BRAF."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9516332/pdf/fonc-12-953013.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446296/
https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-dabrafenib-trametinib-braf-solid-tumors

3. Incorperating Oncolines Data with Historic Clinical Data and FTO

If Bisantrene improves the clinical efficacy of Doxorubicin and Decitabine in 86% and 92% of cancer cell lines, respsectively, which have accurately predicted or described in-human effects approved by FDA standards, I am extemely confident that the risk of creating a significant adverse effect is very low. Furthermore, even if such a risk exists, the potential benefits will far outweigh it.

FTO plays a central role in the hallmarks of cancer and chemoresistance, with connections being made to cancer stem cells, considered the root cause of relapse and resistance. If true, the FTO protein is one of the most influential regulators of efficacy, relapse, and resistance that has never been targeted.

Bisantrene is in a truly unique position clinically where there is so much that one can be learn about this drug, but there is still significantly more that can be learned through inquiry. Clearly, with the new mechanistic discoveries, Bisantrene's clinical history needs to be viewed through the lense of an FTO-inhibitor and not an anthracycline. The response rate for Bisantrene correlates with dose frequency and not dose, where longer durations of dosing (even at lower dose ranges) drive better responses. When adjusted for dose frequency, dose does correlate with response rate. Indicating that there is something else happening when high doses are given over 7-days. I suspect this is a self-synergy of FTO inhibition with the poor anthracene activity, where preclinical models from RAC have proven that Bisantrene decreases the concentration of Anthracyclines required to achieve similar cell killing of Anthracyclines as single agents. This highlights that at high concentrations dosed over 7-days, Bisantrene's FTO-inhibition sensitizes the cancer cells to DNA intercalation (anthracene activity) to self-synergistically kill cancer cells.

Therefore, what Bisantrene can and cannot do in the clinic is yet to be decided, as the dose and dose frequency alone and in combination need to be finalised to optimize the targeting of a protein central to cancer and chemoresistance that has never been actively targeted before.



4. Comparison to known compounds

Bisantrene has comparable efficacy to drug combinations (3-4 drugs) for R/R AML, and is by far the most effective single-agent molecule when comapred to alternatives.



Summary

Yes, there is a risk that increasing m6A levels in cancer could lead to tumor progression, but that is not how the preclinical and clinical data is playing out. The FTO protein controls m6A levels in every cell of our body where cancer originates from, thus every cancer cell will have a level of FTO. It is not yet known what effect Bisantrene will have in the clinic, but if effects like below were achievable 40-years ago, then I'm pretty keen to find out just what targeting a protein found at the core of cancer can do.

10 patients with APL; 9 first relapsed; average 8 prior therapies; 8 patients achieved CR (80% CR)