Racura Oncology recently raised AU$34.3 (US$24.31) million to fund its RC220 clinical programmes in acute myeloid leukaemia (AML), epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer, and anthracycline cardioprotection in solid tumour patients. 

Diana Turner speaks to Dr Peter Smith, Executive Chair of Racura, about the company’s approach to suppressing an ‘undruggable’ target to overcome treatment resistance in cancers. 

DT: You use G-quadruplex (G4) biology in your therapies, yet no G4‑binding ligands have ever made it into routine oncology treatment. What’s different about your approach? 

PS: G-quadruplexes (G4) are three-dimensional structures that form in RNA and DNA in guanine rich sequences. There are potentially hundreds of thousands of sites that could form a G4 although the number that actually form in a living cell is thought to be a small fraction of the potential number. The interest in G4s is that they appear to act as control points or regulators of important and potentially harmful genes such as oncogenes. Cancer is frequently caused by mutations or amplifications in oncogenes and the concept is that if we can manipulate the activity of these regulatory structures, we will be able to switch off the expression of these damaging genes. 

Racura came into this space through the discovery that its drug (E,E)-bisantrene primarily acts through silencing of the MYC gene by stabilising the G4 in the MYC gene promoter. MYC is upregulated in around 70% of all cancers and its principal role in the cell is to switch on all the machinery in the cell needed for cell division. 

G4s have been studied for decades and we are certainly not the first to think of them as drug targets. However, previous attempts have had issues with a lack of selectivity and potency leading to disappointing clinical activity. We now think that this is because a good G4 binder needs to be quite hydrophobic which leads to problems of low aqueous solubility or put another way, a good G4 drug will have inherently poor drug-like qualities. This is where the story gets interesting because (E,E)-bisantrene was never commercialised because of solubility issues and the need to use central line catheter to deliver the drug to patients. The developer at the time (Lederle, now part of Pfizer) had conducted numerous positive clinical studies and it was this clinical data that prompted Racura to reformulate the drug to overcome the solubility issue.  

DT: You recently raised AU$34 million directly from shareholders. Have you found it has been a difficult fundraising landscape? 

PS: The fundraising landscape in Australia at the moment is quite tough and was adversely affected by recent tax changes that will make investing in growth companies less rewarding for investors. Racura’s shareholders are mainly retail investors and they have been incredibly supportive. Most of the AU$34 million was raised through a bonus option issue which was very popular. 

DT: Why do you think there has been a renewed interest in MYC as a target for cancer therapy? 

PS: I don’t think there is renewed interest in MYC as a target, I think it has been a very high profile target since its discovery in 1982. The issue has been finding good drugs to modulate its activity. MYC is a transcription factor and it is a largely unstructured protein that does not provide the typical three-dimensional structures that enable high affinity binding of small molecule drugs. For this reason, MYC is still considered to be ‘undruggable’, although the same was said about RAS until recently. We expect that MYC will be drugged at some point as new techniques and tools become available. Racura is not directly targeting the MYC protein but is silencing the gene through the interaction with the MYC G4. 

DT: You’re targeting acute myeloid leukaemia (AML), epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer, and anthracycline cardioprotection in solid tumour patients. Why were these therapeutic areas chosen? 

PS: Great question! Some of these choices were empirical but turned out to fit perfectly with the MYC mechanism of action. (E,E)-bisantrene was originally approved for AML in France in 1988, but, again, wasn’t commercialised. AML is known to be one of the most MYC-driven malignancies with 90% of all cases having high expression of the protein, so it makes sense that a MYC-silencing drug would work well for this indication. We will initiate Phase III testing of our proprietary formulation of (E,E)-bisantrene, RC220, in AML later in 2026. Lederle’s pursuit of approval for AML was, of course, empirical as they did not know the mechanism – now AML would be a logical choice. 

Protecting cells from the damage done by chemotherapies such as doxorubicin was an empirical discovery made by Racura based on the observation that (E,E)-bisantrene was far less cardiotoxic. It was then found that combining (E,E)-bisantrene with doxorubicin had a protective effect. We can now tie this effect back to MYC – doxorubicin increases MYC in cardiomyocytes leading to double strand DNA breaks which are harmful to the cell, while (E,E)-bisantrene reduces MYC and prevents the DNA damage.  

The third trial we are recruiting is for EGFR mutated NSCLC. This trial was designed, based on the mechanism of action and information in the literature, that MYC expression is associated with resistance to many different targeted therapies. This trial is aiming to delay the emergence of resistance to the leading standard of care drug Tagrisso (osimertinib), by suppressing MYC expression. 

DT: What translational challenges have you had to overcome in developing your pipeline? 

PS: The biggest challenge was reformulating the drug. Lederle had tried to reformulate (E,E)-bisantrene for obvious reasons but failed. It took Racura a long time to get the formulation right, but we had the benefit of significant advances in technology to help us. The new formulation, called RC220, helps to keep the drug from precipitating when delivered by peripheral vein, but when it is in the blood the pharmacokinetics and pharmacodynamics are identical to the original drug. This allows us to get comfort from the earlier clinical data which demonstrated its clinical activity and safety across numerous malignancies.  

DT: What success have you had with your approach so far? When can we expect a G4‑targeting drug to reach clinical practice? 

PS: We are now successfully dosing patients with the new formulation, RC220, without any signs of precipitation. So, the main impediment to (E,E)-bisantrene becoming a successful drug has been overcome.  

With the Phase III trial in AML not too far away, it is possible that RC220 could be approved in around three years. That said, there have been several approvals in NSCLC that were based on early and modestly sized clinical trials, these include zongertinib, sevabertinib and sunvozertinib, so we will be exploring the potential for fast approval in NSCLC from future trials. 

DT: The first patient has been treated in the Phase I HARNESS-1 clinical trial in lung cancer. How are you hoping to overcome treatment resistance in this patient group? 

PS: MYC is associated with the emergence of resistance to a large number of targeted and chemotherapy drugs. This makes perfect sense given MYC’s role driving cell division, i.e. resistance means that some other signalling pathway has taken over driving growth of the tumour. This is definitely the case in EGFRm NSCLC where the tyrosine kinases effectively reduce MYC levels but, on progression, the tumours show increased expression. By silencing MYC, we hope to overcome this resistance or delay its emergence. HARNESS-1 will treat patients who are on osimertinib, AZ’s Tagrisso, who are showing signs of biochemical relapse assessed by measuring circulating tumour DNA (ctDNA). 

DT: Do you have plans to expand to new diseases in the future? How do you see G4‑targeting fitting into future precision oncology? 

PS: We do not have current plans to expand given that we already have three trials exploring different aspects of (E,E)-bisantrene’s biological effects – we need to stay focused. However, the biology is singing to us, with data across multiple targets suggesting that the resistance mechanism is common to a large number of cancers. The literature suggests that a MYC silencing drug should work well in combination with inhibitors of BTK, CDK4/6, ALK, RAS, KIT to name but a few. If we achieve proof-of-concept in the HARNESS-1 trial then, backed by ongoing preclinical work, there could be numerous opportunities across multiple high value targeted drug franchises. 

The post Why G‑quadruplex biology is back and what it means for MYC‑driven cancers appeared first on Drug Discovery World (DDW).