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Disease and treatment

Micromolecules undermine the battle against cancer

Only half the people diagnosed with colorectal cancer survive for more than 5 years. Once the cancer cells become resistant to one type of chemotherapy drug, other types also become less effective. Researchers have now discovered a mechanism for the resistance and can determine who will become resistant, enabling appropriate treatment from the outset.

Colorectal cancer is the third most commonly diagnosed form of cancer in high-income countries. In Denmark, 1 in 20 people get colorectal cancer during their lifetime, and only about half survive more than 5 years. Although treatment has become more effective, resistance to chemotherapy is still a massive problem. Danish researchers from the Research Unit for Molecular Medicine of Aarhus University have now discovered an explanation and a possible solution for the problem.

“We recently discovered that people who were resistant to treatment with oxaliplatin had something in common. They all had a very elevated level of a small molecule: a microRNA that plays an essential role in regulating the metabolism and life cycle of cells, including whether they are sensitive to specific types of drugs,” explains Claus Lindbjerg Andersen.

The first shot must be a bullseye

The microRNA called miR-625-3p is just one of about 1000 known microRNA molecules that regulate how genetic information is converted into proteins in cells. Understanding how colorectal cancer cells become resistant to oxaliplatin required the Danish researchers to try to understand the effects of the elevated level of miR-625-3p and why some but not all people become resistant.

“Our experiments show that miR-625-3p influences the mitogen-activated protein kinases – enzymes that can induce apoptosis, or cell death, when the cells experience various types of stress such as chemotherapy. miR-625-3p seems to slow this process so that, instead of dying, the cancer cells survive. Chemotherapy can no longer stress the cells to induce apoptosis, so resistance emerges.”

The new discovery is especially important mainly because miR-625-3p may function as a useful biomarker. The drugs 5-fluorouracil and leucovorin are usually combined with either oxaliplatin or irinotecan. The clinician decides whether to use oxaliplatin or irinotecan, but from now on measuring the concentration of miR-625-3p will crucially indicate which drug best suits the person being treated.

“When people are being treating for cancer, initiating the right treatment is crucial. This is partly because the cancer can develop further if it is not attacked from the start but, possibly even more importantly, because another chemotherapy drug is often much less effective. So if someone resistant to oxaliplatin is treated with this drug first, then subsequent treatment with irinotecan will be less effective. Hitting the target correctly at the start is therefore essential,” explains co-author and postdoctoral fellow Mads Heilskov Rasmussen.

Resistance can be combated

Progress has been rapid since microRNA molecules were first discovered in humans in 2002. Several of these small molecules appear to play a surprisingly important role in processes connected with such diseases as cancer. Measuring the quantity of a specific microRNA molecule in a person’s cells and organs often indicates whether the person is about to develop cancer and, for miR-625-3p, which drugs should be used in chemotherapy. Research enables anti-microRNA molecules to be used that can inhibit the effect of the small molecules.

“The effects of microRNA molecules have already been inhibited experimentally for other diseases. We have demonstrated that inhibiting miR-625-3p in cell cultures reduces the resistance of cells, thereby also increasing the effectiveness of chemotherapy. Several drug companies are already testing anti-microRNA treatments, and miR-625-3p is an ideal new candidate for testing.”

Now that Claus Lindbjerg Andersen and Mads Heilskov Rasmussen have passed on the baton, they are striving to solve several of the other resistance mysteries within cancer, and much still needs to be solved. “Treating cells with such powerful substances as those used in chemotherapy triggers natural selection pressure that invariably makes cells mutate, and they become resistant to the treatment over time.”

Artiklen “Putting a brake on stress signaling: miR-625-3p as a biomarker for choice of therapy in colorectal cancer” was published in Epigenomics in October 2016.

Artiklen “miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells” was published in Nature Communications in July 2016.

High expression of microRNA-625-3p is associated with poor response to first-line oxaliplatin based treatment of metastatic colorectal cancer” was published in Molecular Oncology in June 2013.

In 2014, the Novo Nordisk Foundation awarded Claus Lindbjerg Andersen a grant for the project Prospective Demonstration of the Clinical Benefit of Monitoring Circulating Tumor DNA following Resection of Colorectal Cancer.