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Iron Levels Target Tumour Drug to Cancer Cells

Written by Vered Smith, Science Writer 

Researchers have altered a pre-existing drug so that it is only activated in RAS-mutated cancer cells.  

Scientists at UC San Francisco changed a current cancer drug to target the high levels of active iron (Fe2+) within pancreatic ductal adenocarcinoma (PDA) cells. This study, published in the Journal of Experimental Medicine, enabled tumour-selective drug activation within cell lines and mice models. In the future, this could result in the development of new, more effective PDA treatments with fewer toxic side effects. 

The Need for Targeted Therapies 

PDA is an aggressive and lethal cancer, with a five-year survival rate of only 9%. The mutation of RAS to KRAS is a characteristic feature of PDA, resulting in constitutive activation of the protein. Consequently, its downstream pathway (RAS-RAF-MEK-ERK) is also constitutively activated.  

Targeting KRAS directly as a treatment has had limited success so far. MEK inhibitors have been approved, but toxic side effects limit the doses given in the clinic. As a result, the doses given are usually only about 25% of the FDA recommended dose, limiting their efficacy.  

Iron metabolism is often dysregulated in cancer. Access to Fe2+ bioavailable iron, as opposed to Fe3+ total iron, plays a role in cancer cell survival and proliferation. The researchers sought to see if they could exploit this knowledge to create a targeted PDA treatment. 

An Iron-Sensing Cancer Therapy 

The researchers found that PDA has a different iron metabolism to normal cells, with higher amounts of labile ferrous iron (Fe2+) in the cytosol. This is associated with a poorer prognosis.  

This increase in Fe2+ accumulation is driven by the oncogenic mutation of RAS to KRAS, which controls the only iron exporter (STEAP3), maintaining a large pool of Fe2+

A Fe2+ mediated Fenton reaction is used in antimalarial drugs, but has never been used in cancer treatment before. In this study, researchers combined the power of this reaction with an approved MEK inhibitor named cobimetinib to create a ferrous iron–activatable drug conjugate (FeADC). They did this by adding on TRX (1,2,4-trioxolane), a molecule that reacts with iron. They named their FeADC TRX-COBI. When TRX-COBI enters a PDA cell with a KRAS mutation and consequently lots of Fe2+, the cobimetinib is activated. However, if there is no KRAS mutation, cobimetinib is not activated. This prevents off-target effects on non-cancer cells. 

Improved Efficacy and Less Toxicity 

TRX-COBI had a similar effect on the downstream RAS pathway, and similar anti-tumour activity to cobimetinib in mice models with PDA. When it was tested on non-cancerous cell lines, they were 10 times less sensitive to TRX-COBI than PDA cells. In contrast, cobimetinib alone was actually more potent in a non-cancer cell line than the PDA cells. 

Additionally, they compared giving TRX-COBI in combination with RMC-4550 (an SHP2 inhibitor) to cobimetinib with RMC-4550. They found that the TRX-COBI combination caused more tumour growth inhibition in mice, but less weight loss.  

This holds exciting clinical potential. As quoted in the press release, a co-senior author Adam Renslo said “By removing toxicity from the equation, you’re talking not just about one new drug, but 10 new combinations that you can now think about exploring in the clinic. That would be the home run for this approach.” 

Image Credit: Canva

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