Cancer Cells Without Fuel

Metabolic processes are the biochemical engine of life. They supply the human body with the energy it needs to live and keep it in equilibrium, or at least they do when the body’s metabolism functions properly. If it malfunctions, it can severely disrupt the body’s balance. That’s what happens in the genesis of cancer. “Metabolism gets reprogrammed to promote the growth of tumors,” Raphael Morscher says.

Morscher is investigating what transpires in the body during tumorigenesis and what biological processes are involved. The physician and molecular biologist works for UZH and at University Children’s Hospital Zurich and is a leading figure in Switzerland’s National Center of Competence in Research (NCCR) Children & Cancer. One of Morscher’s research aims is to learn more about what nutrients cancer cells use and how they process them. This knowledge helps to develop new therapies because if the metabolism of cancer cells can be selectively blocked with precision, the biological engine misfires or even stalls. The cancer then can no longer grow and thus dies.

Conventional chemotherapies try, among other things, to inhibit nucleic acid metabolism because, in order to multiply, cancer cells need to crank up the production of DNA nucleotides before each cell division so that they can pass on their genetic blueprint. Chemotherapeutics prevent this from happening, but they cause partially severe side and knock-on effects. They impact like chemical bombs and inflict collateral damage on healthy DNA. These therapies are essential and save the lives of many patients, Morscher stresses. But they put a huge strain on the body and thus increase the risk of sequelae such as cardiovascular problems or cancer recurrence.

It is important to avert late sequelae as far as possible, particularly in children who are still growing and in those who have a long life ahead of them in the event of being cured. Morscher therefore is working on new therapies that target metabolism and cause less lingering damage. One therapeutic avenue is to strike cancer’s Achilles’ heel by disrupting metabolic processes that solely serve the tumor. This inhibits tumor growth but has fewer adverse effects on the rest of the body. Morscher therefore is investigating, for instance, changes in protein and lipid metabolism that are exclusively vital to the life of cancer cells.

Morscher’s research focuses on pediatric oncology. “Cancer metabolism differs between adults and children,” he says, “so it has to be investigated separately for the two groups.” In adults, the body’s overall metabolism can be adversely affected, for instance, by diseases. Diabetes, for example, considerably elevates the risk of falling ill to cancer of the liver, pancreas or intestines. Such diseases rarely occur in children. Cancer in children is usually caused by genetic mutations in cells during early development. They reprogram the body’s metabolism to enable tumors to grow. Specific mutated genes, called oncogenes, drive tumor growth in children.

Most types of childhood cancers do not occur in adults. One example is neuroblastoma, which afflicts 15 to 20 children per year in Switzerland, most of them no older than six. A neuroblastoma is a malignant tumor that develops from immature nerve cells. Neuroblastomas often grow in the abdominal cavity, in the thorax or along the spinal column in the neck. These tumors remain difficult to treat even today. “Despite high-dose chemotherapy, stem cell transplantation, surgery, radiation therapy and immunotherapy, only half of afflicted children in high-risk cases survive,” Morscher says. That’s why the researcher is looking for new approaches to treating neuroblastoma more effectively. He and his postdoctoral researcher Sarah Cherkaoui showed what direction that could take in a study that made it onto the cover of the prestigious science journal Nature last October under the title “Starving Cancer.” The investigation conducted by the researchers in fact demonstrated that a drug newly approved in Switzerland, in combination with a specific diet, can thwart tumor growth.

The drug’s active ingredient, difluoromethylornithine (DFMO), inhibits the metabolic pathway that produces polyamines essential to the growth of immature cancer cells in children. Those polyamines are formed from the amino acids proline and arginine, which the body ingests through food. If the body is deprived of those building blocks, it can no longer produce enough polyamines, and the tumor stops growing. In experiments with mice, the researchers demonstrated that a diet free of proline and arginine can more than double the drug’s efficacy and largely block further tumor progression.

What’s more, the therapy caused the cancer cells to develop into mature neurons, as they are actually supposed to do. In this sense, the new therapeutic approach ingeniously combines aspects of tumor metabolism with developmental biology in the treatment of cancer. A direct implementation for patients would primarily mean abstaining from eating protein-rich foods like meat, fish, dairy products and legumes while taking amino acid supplementation at the same time. However, compliance with a diet of that kind is hard to enforce in children, Morscher says. That’s why as a next step, the researchers want to develop enzymes that remove the amino acids arginine and proline directly from the bloodstream and thus deprive cancer of the necessary building blocks without having to adhere to a diet. This innovative therapeutic approach is slated to be further investigated next year in a clinical study to be conducted at University Children's Hospital Zurich.

This is only the beginning. Over the next 12 years, the period during which the NCCR Children & Cancer will run, Morscher’s aim is to gain an even more granular understanding of the mechanisms of cancer metabolism to lay the groundwork for further therapies. “Today we have a rough idea of how metabolism functions in different types of tumors,” the researcher says, “but in the future we and our partners want to be capable of analyzing and understanding the metabolism of each individual tumor in detail.” That’s the bedrock for developing new drugs and enlarging the spectrum of promising therapeutic approaches in pediatric oncology, not just for the treatment of neuroblastomas, but also for many other types of cancers in children as well as adults.