Delivering a One-Two Punch to Glioblastoma Tumor Cells

May 31, 2020

In a new study published in the Journal of Clinical Investigation, a multi-disciplinary team led by investigators at Columbia University Irving Medical Center has unraveled the epigenomic underpinnings of the Warburg effect in glioblastoma, honing in on potential therapeutic targets that starve glioblastoma cells and keep them from growing.

The Warburg effect, first observed in the 1920s by biochemist Otto Warburg, describes how cancer cells use sugar (glucose) to fuel their rapid growth via glycolysis, instead of normal cellular metabolic pathways (oxidizing glucose). This phenomenon has been explored as a potential therapeutic target across a number of different cancer types.

In this study, the investigators uncovered that enhancers and super-enhancers – clusters of regulatory non-coding DNA regions that boost genetic transcription–regulate the transporters and enzymes that facilitate the Warburg effect and in turn, glioblastoma growth.

“We probed the glioblastoma metabolism from all sides to find how the glioblastoma metabolism is fueled and impacted by epigenetic changes,” says Markus Siegelin, MD, senior author on the paper and member of the Precision Oncology & System Biology program at the Herbert Irving Comprehensive Cancer Center. 

Previous studies have shown that histone deacetylase (HDAC) inhibitors, a new class of drugs that work to block transcription, may disrupt super-enhancers and stop cancer growth. Armed with the knowledge that the Warburg effect in glioblastoma is maintained by super-enhancers, the researchers tested two HDAC inhibitors, panobinostat and romidepsin in in vitro studies. The team found that these drugs disrupted the super-enhancers in glioblastoma cells, inhibiting the Warburg effect that glioblastoma cells use to grow. Additional studies by the team elucidated new insights into how HDAC inhibitors control glycolysis, providing a foundation for further studies in additional cancer subtypes.

HDAC inhibitors are approved for treating cutaneous T-cell lymphoma and multiple myeloma, but their efficacy in treating solid tumors has proven more difficult. Solid tumors, such as glioblastoma, exhibit metabolic plasticity, whereby tumor cells subvert how they turn fuel into energy in response to changes in their environment. 

“Usually, just a single drug falls short of successful long-term treatment,” says Dr. Siegelin, who is also an associate professor of pathology and cell biology at Columbia University Vagelos College of Physicians and Surgeons. “Even though the drug is successful, tumor cells find a way to circumvent and survive following the treatment.”

In in vitro and in vivo studies, the team found that to account for the lack of glycolysis, the glioblastoma cells instead began depending on fatty acid oxidation (FAO) for growth.

“We were intrigued by the observation that HDAC inhibitors engage in the activation of transcription factors that facilitate oxidative energy metabolism, hypothesizing that these transcription factors drive survival of HDAC inhibitor treated glioblastoma cells,” says Trang Nguyen, PhD, the first author of the study and a postdoctoral research scientist in the Siegelin lab who is funded by the American Brain Tumor Association to perform work on glioblastoma research.

Given that panobinostat (an HDAC inhibitor) and etomoxir (an FAO inhibitor that switches the energy metabolism of cells from fatty acids to glucose oxidation) are either used in the clinical setting or have undergone clinical testing, the researchers tested these as a combination therapy in mouse models of glioblastoma, colon cancer, and melanoma. In all the models, they found that the combination treatment resulted in a significantly longer overall survival or reduction of tumor growth.

“Our study in mice shows promise for a HDAC and FAO inhibitor combination therapy option that could treat a variety of solid tumor types,” says Dr. Siegelin. “The results of our analyses reinforce the potential of targeting the cancer cell metabolism with therapies.”

 “Glioblastoma is a very aggressive, incurable cancer and more effective treatments are urgently needed,” says Jeffrey Bruce, MD, FACS, a co-author on the study and co-director of the Brain Tumor Center at Columbia University Irving Medical Center. “The discovery of novel ways to attack these tumors inspires new hope for our patients.”