During one action of de novo lipid synthesis, SCD converts saturated fatty acids to monounsaturated fatty acids. Previously, Christian Badr, Ph.D., an assistant in Neuroscience at MGH and an assistant professor of Neurology at Harvard Medical School, and his colleagues showed that glioblastoma cells depend on the activation of SCD and the schedule of monounsaturated fats.
In this new research study, the group checked the anti-glioblastoma potential of an SCD inhibitor, YTX-7739, that can cross the blood-brain barrier and is being evaluated as an oral drug in stage I medical trials for the treatment of patients with Parkinsons disease.
The investigators discovered that YTX-7739 was toxic to patient-derived glioblastoma stem cells. By obstructing SCD, the cells collected a lot of saturated fatty acids, a procedure referred to as lipotoxicity. Likewise, when administered to mice with tumors, YTX-7739 inhibited processes associated with fat metabolic process in glioblastoma cells and increased the cells sensitivity to standard glioblastoma chemotherapy.
When taking a look at the in-depth mechanisms behind YTX-7739s impacts on cells, the researchers discovered that the MEK/ERK signaling pathway renders glioblastoma cells especially vulnerable to YTX-7739, whereas the AMPK signaling path acts to safeguard glioblastoma cells and can make them resistant to the loss of de novo lipid synthesis that happens when YTX-7739 exists.
” Based on our outcomes, we propose that MEK/ERK and AMPK activities, which can be detected in tumor biopsies, could be predictive biomarkers to direct client selection and stratification,” states Badr.
To put it simply, patients whose tumors have robust MEK/ERK activity would likely take advantage of therapies such as YTX-7739, whereas those with high AMPK activity likely would not. “Our findings need to also help tailor treatment paradigms to take full advantage of healing effectiveness.
For example, some extensively utilized drugs, such as the anti-inflammatory representative salicylate or the anti-diabetic compound metformin, are powerful activators of AMPK and could be destructive to the effectiveness of YTX-7739 or other de novo lipid synthesis– targeting treatments,” states Badr.
Recommendation: “Targeting de novo lipid synthesis causes lipotoxicity and impairs DNA damage repair in glioblastoma mouse models” by Katharina M. Eyme, Alessandro Sammarco, Roshani Jha, Hayk Mnatsakanyan, Caline Pechdimaljian, Litia Carvalho, Rudolph Neustadt, Charlotte Moses, Ahmad Alnasser, Daniel F. Tardiff, Baolong Su, Kevin J. Williams, Steven J. Bensinger, Chee Yeun Chung and Christian E. Badr, 18 January 2023, Science Translational Medicine.DOI: 10.1126/ scitranslmed.abq6288.
This work was supported by the National Institutes of Health, the Department of Defense, the American Brain Tumor Association, and the Concern Foundation.
The energy requirements of glioblastoma cells are satisfied through the conversion of carbs to fats. An investigational drug named YTX-7739 interrupts this process. In mice with glioblastoma, YTX-7739 was discovered to decrease tumor development and boost the susceptibility of glioblastoma cells to anticancer treatments.
In mouse research studies, the drug was found to postpone the growth of growths and enhance the level of sensitivity of glioblastoma cells to anticancer treatments.
Due to its highly aggressive and deadly nature, glioblastoma, a type of brain cancer, is typically resistant to standard treatments. As a result, scientists are seeking out characteristics of glioblastoma cells that might point to possible targets for drug advancement.
One such particular is the dependence of the cells on de novo lipid synthesis, likewise understood as the conversion of carbohydrates to fats, to meet their energy needs.
New research led by scientists at Massachusetts General Hospital (MGH), an establishing member of Mass General Brigham, exposes that a drug that inhibits the enzyme stearoyl CoA Desaturase 1 (SCD) disrupts this process, and when administered to mice with glioblastoma, the drug delays tumor development and increases glioblastoma cells sensitivity to anticancer treatments. The findings, which are published in Science Translational Medicine, might lead to new treatment choices for clients.
The energy needs of glioblastoma cells are satisfied through the conversion of carbohydrates to fats. In mice with glioblastoma, YTX-7739 was found to slow down tumor growth and improve the susceptibility of glioblastoma cells to anticancer treatments.
The private investigators found that YTX-7739 was hazardous to patient-derived glioblastoma stem cells. When administered to mice with growths, YTX-7739 inhibited procedures included in fatty acid metabolism in glioblastoma cells and increased the cells level of sensitivity to standard glioblastoma chemotherapy.