Cardioprotection thread, page-1179

It’s a COMPETITOR - but its GOOD NEWS for RAC!

Great find @HeyLine! Here is my take!

I think this is actually good news for RAC, even though at first glance it looks like a competitor has emerged. And for the record, competitors worry me coz IMO, if a better product is discovered, it will matter little that RAC is ahead! The shareprice will tank as some head for the exit door. And its not like RAC can easily pick up speed anyway, particularly with resources so limited that we can only focus on the narrow, when the opportunities are abound.

So, are these two MicroRNAs (miRNAs) better products?

A KEY point is that the study in question didn’t involve cancer at all: they used zebrafish embryos and healthy, non-tumour-bearing mice. Doxorubicin was given to induce cardiac injury (cardiomyopathy, oxidative stress, fibrosis), similar to what it does in humans.

It is really key that there was no cancer in these models. So, even from a preclinical point of view, this is further back than it might appear to be. But thats not the important part (and for me - that doesnt stop it overtaking RAC if this was actually a non inferior product).

Just like RAC’s RC220, any new drug aiming to be a companion to doxorubicin has to prove itself. Not just by looking good in a vacuum, but by showing it can be safely and effectively combined with chemo, without undermining the cancer-fighting part. This includes proving it doesn’t make things worse - like making cancer grow faster or become resistant. That’s part of the construct of the hurdle RC220 is addressing in its ongoing Phase 1 and 2 trials, and any new contender will have to jump through the same hoops.

Here’s the kicker: miR-222 and miR-455, the miRNAs being pushed in this study, are already known to promote chemoresistance. How do I know? The paper itself says so:

• “Given reported chemoresistance effects of miR-222 and miR-455, it will be important to determine whether treatment diminishes doxorubicin’s anticancer effects. Methods for confining expression to the heart, including vectors with cardiac tropism and lineage-specific promoter, could circumvent undesired effects on cancer…"

Their suggestion? Find ways to confine the effect to heart cells only, so the cancer doesn’t benefit. That’s a delivery challenge that is yet to be solved!

Further reading does show documented evidence that this wonder pair is a problem;

• miR-222 has been linked to doxorubicin resistance in breast cancer (1), and
• miR-455-3p drives cisplatin and docetaxel resistance in esophageal squamous cell carcinoma (2)! Taken word for word, Liu et al (in Molecular Cancer) state the following: "... miR-455-3pexhibited aberrant upregulation in various human cancer types, and was significantly associated with decreased overall survival of cancer patients..."(2).

The keen eyed and eared might remember the story of Dexrazoxane, which also started as a cardioprotective hero but later ran into trouble in Europe due to concerns about long-term risks, including possible cancer worsening effects. It was later absolved of some of the bad effect, but the parallels are hard to ignore.
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But RACers should not kill this pair! This is an opportunity.

This paper strengthens the argument that cardioprotection during chemotherapy is a serious UNMET NEED. UNMET is an important word!
Lines like “There is a pressing need for cardiac-specific therapeutics that prevent chemotherapy complications without compromising efficacy” are exactly what RAC’s scientific and investor relations teams should be shouting from the rooftops. RC220 (Bisantrene) fits that description perfectly in my view: its a previously approved drug, now with improved formulation, that fights cancer and protects the heart. Unlike these experimental miRNAs, it doesn’t need fancy vectors to avoid causing more harm than good. Arethe Science writers on the case? They better be - use the paper as a platform from which to launch a paper!

Even more striking is the reminder in this paper, that doxorubicin cardiomyopathy has a worse prognosis than ischemic cardiomyopathy, with five-year survival rates below 50%. That’s a sobering statistic, and it validates RAC’s hypothesis: cardioprotection is a clinically valuable endpoint, not just a side benefit. I know Dr T is onto this already, but I think its worth a remention!

This whole idea that is being advanced by these new drugs could also open the door for broader discussions about using Bisantrene instead of doxorubicin in cancers where its efficacy is comparable, avoiding cardiotoxicity altogether: a subject that Dr T seems unkeen to engage in! No issues there, but it will come. Why damage the heart if you dont have to?

In short, while this paper presents a potential “competitor,” it actually highlights the risks of alternative approaches and reinforces RAC’s strategic direction. RC220 is a cancer drug that protects the heart.

These miRNA approaches look like they might protect the heart… but kill the host through accelerating cancer growth! What died first - the heart, or the host?

Ok, before someone calls my last point silly: What I mean to say is that, your heart might still be beating, after your brain has been turned to a cancer mash due to accelerated cancer growth!

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REFS

Note - the articles below are focussed on finding solutions to problem of chemoresistance that these MicroRNAs (miRNAs) cause!

1. Wang H, Deng Z, Chen X, et al. Downregulation of miR-222-3p Reverses Doxorubicin-Resistance in LoVo Cells Through Upregulating Forkhead Box Protein P2 (FOXP2) Protein. Med Sci Monit. 2019;25:2169-2178. Published 2019 Mar 24. doi:10.12659/MSM.913325
2. Liu A, Zhu J, Wu G, Cao L, Tan Z, Zhang S, Jiang L, Wu J, Li M, Song L, Li J. Antagonizing miR-455-3p inhibits chemoresistance and aggressiveness in esophageal squamous cell carcinoma. Mol Cancer. 2017 Jun 21;16(1):106. doi: 10.1186/s12943-017-0669-9. Erratum in: Mol Cancer. 2021 Dec 1;20(1):152. doi: 10.1186/s12943-021-01425-4. PMID: 28633632; PMCID: PMC5479030.