Zantrene: A brief review
Background
Zantrene is owned by Race Oncology (RAC). Developed in the late 1970s to be an anthracycline that is safer for the heart, Zantrene was tested clinically through the 80s and 90s in a range of different blood and solid tumors. While not demonstrating strong clinical efficacy in solid tumors, Zantrene showed some promise in AML (Table 1), Follicular Lymphoma (ORR 56%; CR 31%; PR 25%; n = 16), and Breast cancer (1-4). The AML data led to the drug eventually being approved for use in France, but was never marketed. Due to a series of internal events, the drug was lost and never fully commercialized.
Table 1: A summary of AML trials
In 2016, RAC bought rights to the drug, and completed a P2 proof of concept trial, where there was a 40% ORR (1CR; 3PR) (5). Of the 10 heavily pretreated R/R AML patients, four were classified as extramedullary AML which was the patient population that achieved objective responses (100%). Figure 1 shows an excellent PET scan of a patient’s response to Zantrene.
Figure 1: PET scan of EMD AML patient treated with Zantrene
In 2020, the City of Hope discovered that Zantrene is in fact the most potent inhibitor of the m6A demethylase ‘Fat mass and obesity-associated protein’ or ‘FTO’ protein (6). The screening process investigated some ~250,000 different compounds within the library, and currently preclinical compounds are yet to match the potency of Zantrene for FTO (Table 2).
Table 2: Low nM concentration FTO targeting compounds
There has, therefore, been a shift in thinking regarding Zantrene as a safer anthracycline to the most potent FTO inhibitor, where all of the clinical data to date can and should be attributed to FTO inhibition over anthracycline activity. Looking through the lens of an FTO inhibitor highlights key pieces of preclinical and clinical data as well as challenges the preconceived notions surrounding Zantrene. Many lines of evidence support this line of thinking, which will be summarized herein.
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Preclinical models supporting strong FTO inhibition and poor anthracycline activity
As previously mentioned, Zantrene is currently the most potent inhibitor of the FTO protein. Early preclinical models investigating Zantrene in comparison to other anthracyclines highlight the poor anthracycline activity of the drug. In historic preclinical studies conducted in the 80s, Zantrene was found to have IC50 values for anthracycline activity at uM concentrations, far greater than the nM concentrations achieved for FTO inhibition. In comparison to other approved Anthracyclines (Mitoxantrone & Doxorubicin) as well as compounds that did not achieve approval (Ametantrone), Zantrene was found to perform far worse in preclinical leukemia studies (1-2). If Zantrene was the worst performer of all drugs preclinically, then how was it able to achieve clinically relevant ORR rates that led to approval in France. Comparatively, Zantrene is roughly 126 times more potent at inhibiting FTO than functioning as an FTO inhibitor.
Figure 2: Zantrene (Bisantrene) demonstrating poor anthracycline activity
Further preclinical work has been completed by RAC to confirm the mechanism of action for Zantrene. A recent Melanoma publication showed that Zantrene can kill cells with a very low nM concentration and that the cell killing affinity correlated with FTO expression (Figure 3; 3). Also, further preclinical work into ccRCC demonstrated low nM cell killing in a range of different renal cell models (Figure 4; 4).
Figure 3: Melanoma Zantrene data
Figure 4: Summary of sensitivity of Zantrene to renal cell lines
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Clinical data supporting FTO inhibition
I have made quite compelling summaries of the historic data and the possible influence of Zantrene as an FTO inhibitor in the following posts on social media. Put simply, there are some unusual findings when Zantrene is used; unlike the typical Anthracycline outcome. Without the FTO knowledge, these phenomena are difficult to explain, but when FTO inhibition is applied, I find there to be some interesting interpretations of the data.
https://hotcopper.com.au/threads/pillar-1-fto-new-thread.5839654/page-878?post_id=52698342
https://hotcopper.com.au/threads/pillar-1-fto-new-thread.5839654/page-1247?post_id=54368862
The FTO opportunity
I stopped gathering this data back in early February 2022, but there are 106 articles linking aberrant FTO expression to 28 different cancer types (Table 3) (1-106).
Table 3: Cancers linked to FTO expression
Additionally, there have been multiple papers that have found FTO inhibition synergies with roughly 16 different approved and unapproved chemotherapies (Table 4) (107-131), and FTO expression has been linked to a plethora of diseases including metabolic, neurological, and reproductive (Table 5) (132-217). This is likely due to the central role of FTO in regulating the intracellular methylation/demethylation of m6A mRNA and the cascading effects on genes, proteins, and thus, cellular function in a range of different cells.
Table 4: Summary of synergies with an FTO inhibitor
Table 5: Summary of diseases associated with aberrant FTO expression
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Summary
I’m sure you can agree that Zantrene is a very interesting molecule in a developing space. This review has not included the cardioprotection aspect of Zantrene, as that work is in its infancy, and deserves its own independent review. I am looking forward to the RAC team determining and developing the dose, dosing regimen, patient population, screening tool, and clinical data supporting FTO in humans, as it is currently in its infancy. At the very least, I hope that you found this information interesting.
