Researchers investigate if it is possible to starve triple-negative breast cancer using different drug combinations.
We all know a balanced diet is important. When we are young the correct nutrition is essential to allow us to grow and develop. Would it surprise you to know that cancer cells also need the right kinds of nutrients to grow and divide? Scientists are interested in figuring out how to starve cancer cells as a way to treat cancer. This is really important research for cancers that have limited treatment options, such as triple-negative breast cancer.
What is triple-negative breast cancer?
Triple-negative breast cancers are an aggressive type of breast cancer. It is particularly difficult to diagnose and treat because its molecular characteristics are not well understood. This type of breast cancer does not have certain proteins on the surface of its cells known as receptors. Triple-negative breast cancers do not have estrogen, progesterone, or HER 2 receptors (human epidermal growth factor receptor 2). This is means hormonal therapies or Herceptin will not work for this type of cancer. The only treatment option for triple-negative breast cancer is chemotherapy. Scientists are researching cancer cell metabolism to find new approaches to treatment.
Cancer’s unique metabolism
Tumors are made up of cells that are rapidly growing and dividing. This means that cancer cells have a high demand for nutrients. Cancer cells are really interesting because they don’t get their nutrients in the same way as regular healthy cells. Both cancer and healthy cells use glucose as a fuel to power the cell. In healthy cells, glucose is broken down through a chemical process known as mitochondrial oxidative phosphorylation. This reaction takes place in the mitochondria, it is the powerhouse of the cell after all. Cancer cells use a different chemical reaction to break down glucose, a process known as glycolysis. This shift in metabolism is known as the Warburg effect.
This change in cancer cell metabolism means glucose is being used to produce lactic acid. As a result, glucose is no longer used to make citrate. Cancer cells need citrate as it initiates the Krebs cycle, a series of chemical reactions whose main purpose is to produce energy and precursors for cellular structures, such as proteins and lipids. Cancer cells no longer use glucose to fuel the Krebs cycle, so they are reliant on different nutrients.
Cancer cells need nutrients
Glutamine is one of the most abundant amino acids in plasma and is a key nutrient that is converted into citrate by some cancers. An enzyme known as glutaminase is used to convert glutamine to glutamate and ammonium which are further processed to make citrate.
Some cancers can also break down fatty acids to produce a molecule known as Acetyl-CoA, which is the precursor to citrate. The cells do this through a process known as beta-oxidation. It is clear that cancer cells need nutrients just like we do but what happens when you take those nutrients away?
Putting cancer on a diet
If you have ever tried to diet, the general idea is that you reduce the food you take in and you will stop putting on the pounds, essentially you stop growing. The same is true for a cancer cell, if you prevent cells from taking up nutrients they tend to stop growing or the rate at which the cells divide slows. If you stop eating all together you starve and die, the same is true for cancer cells. The trick is figuring out which nutrients are essential to each type of cancer.
So how do you stop a cancer cell from eating? Drugs known as small molecule inhibitors are used to block certain enzymes from working, an example would be CB-839 – a drug that prevents glutaminase from working and this stops cancer cells from being able to use glutamine.
Researchers explore what nutrients are essential for triple-negative breast cancer
In a recent study published in the Journal of Biological Chemistry, researchers in Brazil wanted to know why some triple-negative breast cancers are resistant to CB-839. The researchers speculated that these cancers must rely on another type of nutrient because they are capable of growing when they cannot process glutamine. The scientists looked at triple-negative breast cancers that were both sensitive and resistant to CB-839. They looked at the differences between the genes in resistant and sensitive cells and found that in the resistant cells, genes for lipid metabolism were active.
The researchers then went on to prove that the resistant cells had increased levels of beta-oxidation. This implicated fatty acids as a possible alternative nutrient source. The scientists went on to treat resistant cells with CB-839 and etomoxir. Etomoxir inhibits an enzyme called carnitine palmitoyltransferase-1 (CPT-1). This inhibition prevents fatty acid metabolism from working. The researchers noted that when the cells were treated with either inhibitor alone the cells had reduced proliferation rates. But when the cells were treated with the combination they began to die.
The data presented holds promise for finding new therapeutic approaches for treating triple-negative breast cancers. The results will also help characterize these aggressive cancers. This will help doctors diagnose and provide the best treatment options to patients. It is important to note that all the research presented in this study was done in cells. Although the results are promising, the work needs further testing in both animal models and in clinical trials.
Written by Tarryn Bourhill Msc, Phd Candidate
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