Tumors can use two common nutrients in the body to block the efforts of current targeted therapies designed to treat glioblastoma (GBM) patients, according to a new study funded in part through the Defeat GBM Research Collaborative. This finding could be used to help develop more effective treatment approaches for GBM patients moving forward.
Launched in 2013, Defeat GBM is a subsidiary of the National Brain Tumor Society. Defeat GBM is a multi-institutional, global collaboration with an ambitious five-year goal to double the survival rate for GBM patients.
The study, published in a recent issue of the Proceedings of the National Academy of Sciences (PNAS), 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.
Dr. Paul Mischel of Ludwig Cancer Research, and a member of the Defeat GBM Research Collaborative, led the study. Dr. Webster Cavenee (Ludwig Cancer Research) and Dr. Timothy Cloughesy (UCLA), also leaders of Defeat GBM, participated in the study alongside Dr. Mischel.
The New Study
Cancer researchers have long known that the metabolism of tumor cells is different from the metabolism of healthy cells. Recently, scientists found that changes to a tumor’s metabolism can occur when a specific enzyme known as mTORC2 is turned on in its cells. mTORC2 plays a key role in regulating a cell’s metabolism, so when it is turned up in tumors it leads to a hyperactive metabolism. This altered, hyperactive metabolism causes cancer cells to take in more glucose and acetate, which provide the excess fuel and energy that tumors need to continue growing uncontrollably.
In the new study Dr. Mischel and colleagues found for the first time that glucose and acetate also affect mTORC2. Dr. Mischel explains that this creates a two-way street in tumors, where mTORC2 can change a tumor’s metabolism, and metabolites (nutrients) like glucose and acetate can, in turn, change mTORC2.
The researchers experimented by testing what happens to GBM cells when they added in the two nutrients. They observed that that at least one of the nutrients was needed in order to turn on mTORC2. The researchers then looked at glioblastoma cells that had a specific mutation in a gene called EGFR. Glioblastoma cells with a mutation to their EGFR gene also turn on mTORC2. Importantly, when the GBM cells had no glucose or acetate added, drugs designed to specifically target the mutation in EGFR (EGFR inhibitors) were able to turn off mTORC2 and slow tumor growth. But when glucose and acetate where added, the drugs stopped working, mTORC2 stayed on, and the tumor grew.
Lastly, the researchers were able to find how glucose and acetate activate mTORC2. The two nutrients create a molecule called acetyl-CoA, which alters a key protein in the chain that makes up mTORC2, thereby turning it on. Additionally, the team found that when mTORC2 is turned on it can, itself, inhibit the enzymes that would typically reverse this process. Therefore, mTORC2 is able to preserve its own activity.
Together, these experiments demonstrated that glucose and/or acetate can turn on mTORC2 by producing acetyl-CoA, which enables tumors to resist targeted therapies. mTORC2, in turn, drives tumor growth by regulating metabolism and other processes that GBM cells use to grow.
The problem is twofold. These nutrients on their own can turn on a process inside GBM cells that accelerates tumor growth and aggressiveness. What’s more, they can be harnessed independently by GBM cells to keep up a hyperactive tumor metabolism that won’t respond to treatment efforts.
Attribution: Carrie Treadwell, National Brain Tumor Society’s Chief Research Officer and Managing Director of Defeat GBM
What it Means
The findings provide new insights into potential treatment strategies for glioblastoma patients.
First, the results suggest that developing effective drugs that target mTORC2, and combining them with the EGFR inhibitors, may be a way to improve survival for glioblastoma patients.
Additionally, while Dr. Mischel notes that the study does not point to the value of any particular diet for helping fight GBM, he offers that his lab is beginning to think about how modifying diets could affect the production of these and other nutrients that influence tumor metabolism.
Finally, Mischel offers that this study suggests that there may be more of a relationship between genes involved in cancer (cancer has long been recognized as a disease of the genes) and the environment than previously thought. In other words, glioblastoma may be influenced by a combination and interaction of genetic and non-genetic factors.
“It is going to take diligent and careful work to determine how lifestyle changes, including diet, can alter tumor cell metabolism,” said Dr. Mischel. “We are actively studying this process and hope that this information can be used to develop more effective prevention and treatment strategies for cancer patients.”