Breaking a cancer cell cycle with two commercially available protectors causes tumor cell death

With two commercially available protectors, the cell cycle of cancer cells in childhood tumor neuroblastoma can be broken down at a key point causing tumor cell death.

Neuroblastomas are hard malignant tumors that usually occur in early childhood. They arise from degenerated neural cells of the sympathetic nervous system.

One prognostic marker for assessing tumor malignancy is the MYCN oncogene. High-risk neuroblastoma patients often develop MYCN, ie very high levels of this protein, which leads to unregulated tumor growth. On the other hand, blocking MYCN or its function could be a promising therapeutic opportunity.

An important step towards this path was taken by an international research project led by scientists from the Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, published in the magazine recently Cancer of nature.

News about the place of MYCN in the cell cycle

The lead author of the publication is Dr Gabriele Büchel from Chair of Biochemistry and Molecular Biology at JMU Biocentre. The lead researcher explains: “Until now, MYCN was known to control the activity of RNA polymerase. This reads the DNA in the nucleus of cells and converts it to mRNA. Through our research , we were able to show that MYCN also plays a special role during the S phase of the cell cycle, when DNA is also duplicated. “

In this stage, therefore, two processes occur simultaneously: DNA reading and reproduction. Strictly speaking, according to Gabriele Büchel, “two trains are on the same route”.

Goal: Promote a rewrite-replica conflict

Together with doctoral student Isabelle Roeschert, she discovered that MYCN prevents the crashes of both trains – a repetitive transcription conflict.

This symptomatic effect requires both Aurora-A and ATR enzymes, and both can be prevented by conventional medications. In this way, targeted “train crashes” can be induced to damage the tumor cell. Or medically: the combination of the two drugs leads to DNA damage and cell death – especially in tumors, while other tissues are unaffected.

“In mouse models of neuroblastoma, we were able to restore tumor growth using this strategy. Some of the experimental animals could be cured even with the combination treatment,” Gabriele Büchel explains. clarify the effect of this “therapy”.

Clinical trials already on the horizon

According to her, patients could also benefit from the experience gained soon. “The products we use are already commercially available. Aurora A and ATR protectors as well as the combinations we currently use are being tested in a number of closer practical models. If they are successful there, clinical trials could begin soon, “Büchel states.

In addition to the JMU working group, research teams from the Charité in Berlin, the Universities of Göttingen and Zurich and the Institute for Cancer Research in London were involved in the study. It was funded by the German Cancer Support and the European Research Council.