An innovative way to treat bone tumors – depleting cancer cells of the energy they need to grow – could one day provide an alternative to a commonly used chemotherapy drug without risk side effects, suggests a new study from the University of Washington School of Medicine in St. Louis.
Examining human cancer cells and mice, the researchers said a two-drug combination aimed at tumor energy sources could be as effective and as toxic as methotrexate, a chemotherapy drug that has long been used to given in high doses to treat osteosarcoma, bone cancer.
The study will appear on January 26 in the magazine Cell reports.
Osteosarcoma is the most common tumor of the bone in adults and children. It makes up about 4% of all pediatric cancers and more than half of all pediatric bone cancers. Routine treatment for osteosarcoma includes surgery, radiation, and a cocktail of chemotherapy drugs including high-dose methotrexate, which can cause liver and kidney damage.
We are interested in developing treatments that kill cancer cells without damaging healthy cells, which can avoid the side effects of traditional chemotherapy. “
Brian Van Tine, MD, PhD, Lead Author Study and Associate Professor of Medicine, University of Washington
“In high doses, methotrexate can lead to liver failure and the need for renal dialysis. We would like to get rid of the methotrexate in this regimen and introduce targeted metabolic therapy that would shorten the treatment, which would reduce the side effects and potential elimination of the need for several hospitals. “
The researchers studied a study drug called NCT-503, a member of a relatively new class of drugs called PHGDH inhibitors that has raised interest as potential metabolic therapies for cancer. Metabolic therapies focus on the chemical reactions that cancer cells perform to sustain life.
This study drug prevents cancer cells from producing the amino acid serine, an energy source that stimulates cancer growth. Loss of serine production stops cell division but does not kill cancer cells.
Unfortunately, osteosarcoma cells can then quickly transform and turn to another energy source, said Van Tine, an oncologist who treats patients at the Teen and Adolescent Sarcoma program at the Siteman Cancer Center at Barnes-Jewish Hospital and Siteman Kids at St. Mary’s Children’s Hospital Louis, both at the University of Washington School of Medicine.
Examining the cells that are changing to be treated with this drug, the researchers revealed a way in which the metabolism of the cells shifts to try to burn another type of fuel. Without serine, the osteosarcoma cell cannot move through its normal metabolic cycle, so parts of that cycle build up.
A buildup of these cellular components – which includes fat, other amino acids, and waste products – then activates a metabolic sign molecule in the middle called mTORC1. Stimulation of mTORC1 causes the cell to begin burning all excited products.
Therefore, the researchers added a second drug that blocks mTORC1. Now extracted from both serine and a secondary fuel source, the cancer cells starved to death and died.
“When we added an mTORC1 inhibitor, we were suddenly able to control tumor growth in mice for a long, long time when the cells were switching to treatment with either drug on their own,” he said. first author Richa Rathore, Ph.D., who had just completed her doctoral studies in the Van Tine laboratory.
The inhibitor mTORC1 is called perhexiline and has been used since the 1970s to treat angina or chest pain. It has recently been studied as a treatment for certain types of heart failure.
The researchers studied mice infected with human osteosarcoma tumors. In mice receiving either drug alone or controlled treatment, the tumors increased in size by nearly 800% over less than 30 days. In contrast, in the mice receiving the two-drug combination, the tumors grew in size by only 75% over 30 days.
“We are still working to maximize these drug treatments, but we hope to be able to take these findings to a clinical trial,” Van Tine said. “In the future, we would like more treatments increased metabolism so that we can one day eliminate the remaining chemotherapy drugs that these patients still receive. The ultimate goal is to transform by pursuing the inherent metabolic properties. to osteosarcoma and a move away from the classic drugs that harm the whole body. “
Source:
Washington University School of Medicine
Magazine Reference:
Rathore, R., et al. (2021) Metabolic compensation activates pro-survival mTORC1 signaling 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma. Cell reports. doi.org/10.1016/j.celrep.2020.108678.