Researchers at Linköping University explain how two important proteins linked to cancer can be prevented from cooperating with each other. The discovery points the way toward future drugs to combat neuroblastoma in children. Their study has been published in the journal nature communication.
Maria Sunnerhagen, professor of structural biology at Linköping University, says, “Today we can treat many cases of childhood cancer that were incurable ten years ago. But there is still a significant group of childhood tumors that evade treatment. Researchers in this field are looking for ways to influence cancer cells when nothing else works.”
His research group has spent several years researching a family of proteins called MYC proteins, which play a key role in the development of many types of cancer. In the current study, they focused on N-MYC. The N stands for neuroblastoma, the form of cancer in which the protein was first discovered. Neuroblastoma is an uncommon tumor disease of the nervous system that almost exclusively affects children under two years of age. About half of children have high-risk tumors that have a low chance of being cured. N-MYC is associated with poor prognosis in neuroblastoma.
Drugs that inhibit MYC have the potential to be an important advance in cancer treatment. However, they have proven so difficult to develop that MYC proteins are often described as inherently “inconvenient”.
Maria Sunnerhagen says, “Classic medical drug development is based on the fact that there is a pocket on the protein that you block with a molecule that is bound there, like Lego bricks that fit together. But MYC keeps changing shape.”
Most proteins have a certain three-dimensional structure that usually contributes to their function and how they interact with other proteins. MYC is different and actually has no definite three-dimensional structure. The protein is flexible and constantly changing shape, which poses a challenge for researchers trying to understand how the MYC protein works.
Additionally, MYC proteins are involved in processes necessary for healthy cells to grow and divide. To avoid harming all cells in the body, it is important that a drug only blocks the MYC function that is problematic in cancer cells, and nothing else. In other words, it takes a molecule that specifically affects a certain interaction between N-MYC and other proteins.
In the current study, the researchers focused on the protein Aurora A, which also has a role in neuroblastoma and several other tumor forms. Preventing these proteins from interacting with each other has been suggested as a way to treat childhood tumors.
“To prevent an interaction, you need to know where it is happening. Despite the fact that N-MYC constantly changes shape, we now know where the two proteins bind to each other. This gives clues to what the drug should look like. We have also found a small molecule that manages to cleave the protein, which lays a good foundation for future clinical trials,” says Johanna Hultman, a PhD student in the same research group at Linköping University.
The elusive N-MYC protein was a worthy opponent and posed a real challenge to researchers seeking to characterize it. To succeed, researchers from the Departments of Physics, Chemistry and Biology at Linköping University collaborated with the research group of Professor Linda Penn at the University of Toronto in Canada on an interdisciplinary study. They used several different methods, such as nuclear magnetic resonance (NMR), AI calculations, and molecular analysis of protein function.
“We are very pleased that in this particular case, which is relevant to childhood cancer, we have gained some more understanding about how these proteins find each other and bind to each other. We can now hand the baton to other researchers working in clinical cell biology and pharmacology to find out whether it is possible to take this forward for drug development,” says Maria Sunnerhagen.
The authors gratefully acknowledge funding from the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Fund, the Canadian Institutes of Health Research, the Swedish National Graduate School for Neutron Scattering in Sweden within the Swedish Foundation for Strategic Research (SSF), and the European Research Council.
