Tumor Metabolism

Cancer researchers have long known that the metabolism of tumor cells is different from the metabolism of healthy cells. As part of this process, tumors undergo a major shake-up to how their cells consume and utilize the fuel they need to sustain their growth and progression. This is known as “metabolic reprogramming,” as the cancer cell’s metabolism is uniquely altered.

Past NBTS-funded research helped identify the unique ways in which different mutations and alterations commonly found in gliomas lead to this reprogramming, and, critically, how tumors become dependent, or “addicted,” to certain molecules in doing so — which has important implications for developing new treatment strategies.

Current Funded Research

NBTS currently does not have active grants in tumor metabolism research. Recently completed projects included a grant to Dr. Kendra Maass at Heidelberg University Hospital (Germany), which conducted advanced analyses of ependymoma tumors and discovered vulnerabilities in these tumors that can be exploited by lipid metabolism inhibitors such as fluoxetine (Prozac). Activities have begun to translate these findings into a clinical trial at Heidelberg University Hospital and international partners. Similarly, an NBTS grant to Dr. Paul Mischel at Stanford University furthered the field’s understanding of aspects of tumor metabolism. Dr. Mischel’s lab made progress studying the underlying biology that drives brain tumor cell growth and survival for the purpose of developing new therapeutics. They discovered an aspect of altered tumor metabolism that contributes to GBM growth and now provides a targeted pathway for further drug development. The Mischel lab has also advanced the field’s understanding of how ecDNA drives medulloblastoma and GBM growth and, in doing so, uncovered potential new therapeutic targets for drug development.

Past Funded Research Highlights

• NBTS-funded research found that the nutrients glucose and acetate can activate a protein that re-programs a cancer cell’s metabolism, which causes tumors to grow rapidly and avoid targeted treatments. These nutrients on their own can turn on a process inside GBM cells that accelerates tumor growth and aggressiveness, and they can be harnessed independently by GBM cells to keep up a hyperactive tumor metabolism that won’t respond to treatment efforts.
  
• NBTS-funded research discovered how glioblastoma cells exploit the brain’s unique metabolism to import vast amounts of cholesterol, which they become “addicted” to, and, importantly, how attacking the mechanisms these tumors use to do so may halt this cancer’s growth. 
  
• NBTS-funded research found a potential missing link – and enzyme called LPCAT1 – between how the most common mutation found in GBM cells, called EGFRvIII, and metabolic reprogramming conspire to drive tumor growth by changing the physical structure of tumor cell membranes. Tumors become dependent on this altered membrane structure for continued growth, but the research indicates that targeting and knocking out LPCAT1 significantly extended the survival in laboratory models of glioblastoma. These results indicate that LPCAT1 can be considered a “very compelling new drug target.”
  
• NBTS-funded research discovered that a molecule called NAD, which is so important to a cell’s metabolism and other functions that healthy cells have three different ways of generating it (NAD), is only able to use a single production pathway in cancerous cells, rendering them highly vulnerable to targeted treatments that block that pathway. 
  
• NBTS-funded research found that the antidepressant drug, fluoxetine (common brand name: Prozac), potently targets tumor metabolism and inhibits EGFR signaling, triggering the killing of GBM cells. Dr. Mischel’s research also found that “combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice.” These findings need to be tested in a prospective human clinical trial.