Metabolic Enzyme Inhibition May Help Treat Melanoma

Melanoma is an aggressive form of skin cancer originating in melanocytes, specialized skin cells residing deep within the epidermis. This specific form of cancer spreads relatively quickly, with tumors often changing shape within a few weeks. Due to this cancer’s severity, researchers have attempted to identify reliable and quick treatment alternatives for individuals diagnosed with melanoma.

Most of the work thus far has focused on depriving tumors of nutrition but often results in lackluster findings. When one source of nutrition is removed, cancerous cells often find new ways to leech nutrients from the body.

However, a team from the Sanford Burnham Prebys Medical Discovery Institute in San Diego, California, took a different approach to treating melanoma. They specifically examined how inhibiting or activating a particular metabolic enzyme impacted melanoma’s growth and tumor formation. Their work, published in Nature Cell Biology, revealed some insightful discoveries about how this enzyme, called GCDH, may work well in restricting cancerous cell growth.

“If we inhibit [GCDH], it leads to changes in a key protein, called NRF2, which acquires its ability to suppress cancer,” says Ze’ev Ronai, Ph.D., professor and director of the NCI-designated Cancer Center at Sanford Burnham Prebys. “Now, our goal is to find a drug, or drugs, that limit GCDH activity, potentially new therapeutics for melanoma.”

GCDH, or Glutaryl-CoA Dehydrogenase, plays a significant role in the metabolization of lysine and tryptophan, which are both amino acids crucial for human health. When the Ronai lab first began investigating how melanoma cells generate energy from lysine, they discovered that GCDH played a significant role.

“Melanoma cells ‘eat’ lysine and tryptophan to produce energy,” says Sachin Verma, Ph.D., first author and 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.”

Additionally, the team found that inhibiting GCDH in animal models gave the protein NRF2 new functionalities that suppress cancer development. “We’ve known for a long time that NRF2 can be both a driver and a suppressor of cancer,” says Ronai. “We just didn’t know how we convert NRF2 from a driver to suppressor function. Our current study identifies the answer.”

The researchers’ findings were surprisingly selective for melanoma tumors, with no impact on lung, breast, or other cancers that they examined in their work. This is likely because these other cancers rely on different enzymatic functions to grow and develop. They also found that normal cells without GCDH were primarily unaffected by these alterations, further suggesting that GCDH could have therapeutic promise.

For future work, the Ronai lab is working alongside scientists at the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys to learn more about small molecular GCDH inhibitors that could act as a starting point for the treatment of melanoma.

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