Some oncology experts are heralding the results of a recent study as a scientific breakthrough with the potential to foster new treatments for melanoma.
Researchers out of Sanford Burnham Prebys in California demonstrated that inhibiting a key metabolic enzyme can kill cancer cells and halt tumor growth in patients with melanoma – the first time such evidence has been found.
These researchers believe that their findings could be used to develop a new class of drugs that are much more capable of treating melanoma. Let’s take a detailed look at this study, which was published in the journal Nature Cell Biology.
What Is Melanoma?
The most severe form of skin cancer, melanoma, results from abnormalities in the cells that produce melanin, the substance in your body that produces eye, hair, and skin pigmentation.
In healthy individuals, new skin cells typically replace older ones by pushing them to the skin’s surface, where they die. However, new skin cells sometimes develop abnormalities that cause them to grow at an exponential rate, which can create a large area of cancerous cells.
While melanoma’s precise cause remains a matter of debate, past research has implicated ultraviolet (UV) radiation from sunlight and tanning beds in the etiology of the disease. However, while most skin cancers develop in areas with more sunlight exposure, people with darker skin often develop melanomas in areas like the palms and soles of the feet with little sunlight exposure.
How Common Is Melanoma?
Skin cancer is by far the most common form of cancer. Although melanoma represents only about 1% of skin cancers, it is responsible for a large majority of skin cancer deaths. According to the American Cancer Society, each year nearly 100,000 new cases of melanoma are diagnosed and about 7,650 people die from the disease.
Melanoma Enzyme Dependence
This new study examines how the growth of melanoma depends on Glutaryl-CoA dehydrogenase (GCDH), an enzyme that facilitates the metabolization of lysine and tryptophan, essential amino acids that melanoma cells often consume for energy.
The researchers found that inhibiting GCDH can spark a structural change in a protein called NRF2. When inhibited, NRF2 can suppress cancerous cells. Study author Ze’ev Ronai, PhD, says that while researchers were already aware that NRF2 can be both a driver and suppressor of cancer, they were unaware of how to convert the protein from a driver to a suppressor. This study may have found the answer to that question.
Inhibiting GCDH Could Starve Tumors
Because various forms of cancerous tumors grow quickly and require fuel to spread, oncologists have been researching ways to starve them. However, past research on the subject has been unsuccessful; when cancer cells are denied one fuel source, they will often quickly find another.
In exploring how melanoma cells produce energy from lysine, this study’s researchers found that GCDH was vital to this process, which requires cancer cells to quell toxic waste that the process produces. Researchers expected this to be a six-step process that would require six different enzymes. However, the study showed that only GCDH was essential and that melanoma cells are incapable of surviving without GCDH in the pathway.
This evidence was found through animal experiments showing that inhibiting GCDH resulted in NRF2 cancer-suppressing properties.
Could This Strategy Work for Other Cancers?
In the oncology world, the findings of studies focused on particular cancers can sometimes be used to develop similar treatments for other forms of cancer. Unfortunately, that is not the case with this study.
The authors discovered that inhibiting GCDH selectively targeted melanoma tumors. Other experiments on breast, lung, and other cancers did not yield similar results. The researchers have posited that these other cancers might rely on other enzymes to spread.
Developing Melanoma Treatments Based on These Findings
The researchers have stated that their next step is to find drugs that limit GCDH activity, which could potentially be used as a new treatment for melanoma. The study may have revealed a few different therapeutic options.
The animal models without GCDH were essentially normal, but were intolerant of high-protein diets. Melanoma patient tumors are also often low in GCDH. The authors believe that because of GCDH’s role in processing proteins, GCDH-poor tumors could be vulnerable to foods that are high in protein. Thus, a dietary treatment could be possible through select protein diets.
Scientists from the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys are now working to identify small-molecule GCDH inhibitors, which could be a springboard for developing future melanoma treatments. The study used genetic methods for inhibiting GCDH, which the authors believe provides proof of concept to seek out these small-molecule inhibitors.