A new study by researchers at the University of California, San Francisco (UCSF) found that cells with oncogenic KRAS mutations have elevated levels of a specific type of iron. This iron may be used to activate drugs that target cancer cells, avoiding harm to normal, healthy individuals.
Cancer therapies limited by toxicity
genes known as oncogenes, the most well-known being KRAS, found in 20% of human cancers. These genes are particularly common in acute myeloid leukemia, lung adenocarcinoma, and pancreatic ductal adenocarcinoma (PDA). When mutated, KRAS genes are implicated in uncontrollable cell proliferation and cell signaling, which ultimately enhance cancer survival. However, such therapeutics have been developed with the aim of
Cancer cells addicted to iron
Homeostasis at metal ion has become a hot topic of research in the cancer industry since the early 1970s. Specifically, the UCSF research team leveraged new discoveries that cancer cells have elevated levels of iron, Fe2+. Ferrous iron [Fe2+] can donate electrons in biochemical reactions that the cancer cell needs to survive and is therefore a major factor in many enzymes.
KRAS-related tumors with increased expression of genes are involved in iron uptake and metabolism, according to transcriptional studies. Specifically, this increase iron concentration was linked with shorter survival times in patients.
According to Collisson, the jury is still curious why KRAS-driven tumors show increased iron uptake and metabolism. Most cancers, particularly those with activated KRAS, have found high levels of ferrous iron, likely to meet the elevated metabolic needs of the cancer cell. Many of the enzymes required for DNA synthesis and repair for example require iron as an essential co-factor.
Researchers at the University of California believe that it may be possible to utilize this feature of PDA cancer cells to their advantage. Could they be selectively targeted by ferrous iron, otherwise called ferrous iron-activatable pharmaceutical conjugates (FeADCs)? Briefly, these are our modern versions of time proven medicines that have a harmful effect. By making iron activated versions of these medications, we inactivate them in healthy tissues. Cancer cells preferentially activate the FeADCs because they have high iron levels, according
Selectively targeting iron-hungriged cancer cells
The scientists used a FeADC version of a US Food and Drug Administration (FDA)-approved MEK inhibitor, cobimetinib. To create the drug, they first identified a specific component of the drug molecule at which the synthetic introduction of an iron sensor would inactivate the drugs activity temporarily, but would not affect its distribution.
In vivo experiments, researchers examined whether the FeADC would be able to disperse KRAS signaling pathways and block cancer cell growth without posing adverse effects on healthy cells and tissues. In general, the mouse models of KRAS-driven cancer, like PDA and lung adenocarcinoma, are difficult to treat. When asked to discuss the validity of the models against human cancer, Collisson said.
Across in vitro and in vivo experiments, scientists found that TRX-cobimetinib facilitated tumor growth to the same level as cobimetinib without causing any harm to healthy cells. As such, they combined TRX-cobimetinib with other anticancer medications and discovered that the combination of therapeutics was even more effective at inhibiting tumor growth, again, without adverse side effects.
The modifications we make to drugs will likely have positive impacts on solubility, distribution, and to some extent excretion. These will need to be evaluated and optimized in animals and then individuals, according to Collisson.
According to Collisson, teams'' positive results have led to their FeADC technology being licensed by a commercial company that will conduct human tests in two to three years.
The UCSF team is focused on expanding the use of cancer cells to increase ferrous iron, and whether this technique may be pharmacologically enhanced in order to further intensify the effects of FeDACs.