For the first time, Sanford Burnham Prebys researchers under the direction of Ze’ev Ronai, Ph.D., have demonstrated that blocking a crucial metabolic enzyme specifically kills melanoma cells and slows tumor growth. These results, which were published in Nature Cell Biology, could lead to a new class of drugs that can be used to treat only melanoma, which is the most dangerous type of skin cancer.

Professor Ronai, who also serves as the center’s head of the NCI-designated Cancer Center at Sanford Burnham Prebys, explains, “We found that melanoma is addicted to an enzyme called GCDH.  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.”

Researchers have been looking into ways to starve cancer cells since tumors expand quickly and need a lot of nourishment. Although this strategy seems promising, the outcomes haven’t been great. Cancers always find other food sources when they are denied one.

Lysine and tryptophan, two amino acids crucial for human health, are metabolized in large part by GCDH, also known as glutaryl-CoA dehydrogenase. The Ronai lab discovered that GCDH was crucial when investigating how melanoma cells produce energy from lysine.

According to Sachin Verma, Ph.D., a postdoctoral researcher in the Ronai lab and the study’s first author, “melanoma cells ‘eat” lysine and tryptophan to produce energy.”

However, in order to use the energy from this pathway, cancer cells must put out the harmful fires created by the 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.” 

Further research revealed that blocking GCDH in an animal model resulted in NRF2’s ability to suppress cancer.

“We’ve known for a long time that NRF2 can be both a driver and a suppressor of cancer,” adds Ronai. “We just didn’t know how we convert NRF2 from a driver to suppressor function. Our current study identifies the answer.”

The study also discovered that blocking GCDH has a selective effect on melanoma tumors. Similar initiatives in breast, lung and other malignancies were unsuccessful, likely because those tumors might be addicted to different enzymes.

From a therapeutic perspective, the study suggests a number of alternatives. Despite the fact that GCDH-deficient animal models appeared to be otherwise healthy, they were unable to digest a diet rich in protein. This is noteworthy since the tumors of certain melanoma patients also have low GCDH levels. The enzyme’s job is to break down proteins, so the authors think that GCDH-poor tumors may also be weak against high-protein foods. This could lead to a treatment that uses food. Select protein diets may also be used as a supplement to lower GCDH levels in tumors.

Inhibiting GCDH has a great deal of therapeutic potential. The majority of normal cells are unaffected by the absence of GCDH, hence GCDH inhibitors would be highly specific to melanoma cells. In order to find small molecule GCDH inhibitors that may serve as the basis for future melanoma therapies, the Ronai group is currently collaborating with researchers at the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys.

“In the study, we used genetic approaches to inhibit GCDH, which provide the proof of concept to search for small molecules inhibitors,” adds Verma. “Indeed, we are actively searching for potential drugs that could inhibit GCDH, which would be candidates for novel melanoma therapies.”

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