LA JOLLA, Calif. — New treatments for melanoma, the most severe form of skin cancer, could be on the way after a major scientific breakthrough.
Researchers at Sanford Burnham Prebys in California have shown for the first time that inhibiting a key metabolic enzyme kills cancer cells and stops tumor growth. The research, published in the journal Nature Cell Biology, reveals that the findings could lead to a new class of drugs to selectively treat melanoma.
Skin cancer is the most common form of all cancers. Although melanoma accounts for only one percent of skin cancer cases, it causes a large majority of skin cancer deaths.
“We found that melanoma is addicted to an enzyme called GCDH,” says Ze’ev Ronai, professor and director of the NCI-designated Cancer Center at Sanford Burnham Prebys, in a media release. “If we inhibit the enzyme, it leads to changes in a key protein, called NRF2, which acquires its ability to suppress cancer. Now, our goal is to find a drug, or drugs, that limit GCDH activity, potentially new therapeutics for melanoma.”
Taking away GCDH starves tumors
Since tumors grow rapidly and require lots of “fuel” in order to spread, scientists have been investigating ways to starve cancer cells. However, as promising as the approach may be, the results have been less than stellar. When doctors deny one food source, cancer typically find another quickly.
Prof. Ronai explains that Glutaryl-CoA Dehydrogenase (GCDH) plays a “significant” role in metabolizing lysine and tryptophan. These are amino acids which are essential for human health. When the team began studying how melanoma cells generate energy from lysine, they discovered that GCDH was “mission-critical.”
“Melanoma cells ‘eat’ lysine and tryptophan to produce energy,” says first author Sachin Verma, Ph.D., a postdoctoral researcher in the Ronai lab. “However, harnessing energy from this pathway requires cancer cells to quench toxic waste produced during this process. It’s a six-step process, and we thought the cells would need all six enzymes. But it turns out only one of these enzymes is crucial, GCDH. Melanoma cells cannot survive without the GCDH portion of the pathway.”
Animal experiments revealed that inhibiting GCDH produced NRF2 cancer-suppressing properties.
“We’ve known for a long time that NRF2 can be both a driver and a suppressor of cancer,” Ronai says. “We just didn’t know how we convert NRF2 from a driver to suppressor function. Our current study identifies the answer.”
The treatment fails with other cancers
Study authors also found that inhibiting GCDH selectively targeted melanoma tumors. Similar experiments in lung, breast, and other cancers did not produce the same impact. The team believes those cancers may rely on other enzymes. The team adds that GCDH-poor tumors may also be vulnerable to high-protein foods, setting up a potential dietary treatment for skin cancer.
The Ronai lab is now working with scientists at the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys to identify small molecule GCDH inhibitors that could be the starting point for future melanoma treatments.
“In the study, we used genetic approaches to inhibit GCDH, which provide the proof of concept to search for small molecules inhibitors,” Verma concludes. “Indeed, we are actively searching for potential drugs that could inhibit GCDH, which would be candidates for novel melanoma therapies.”
South West News Service writer Stephen Beech contributed to this report.