Researchers at Boston University School of Medicine’s Department of Dermatology published a paper in “Cancer Research” last month on YK-4-279 — a promising drug with the potential to become a therapeutic agent in the treatment of melanoma.
Deborah Lang, associate professor of dermatology at BUSM, said she led research over the course of several years, including before coming to BU. Her laboratory team’s research survived the move from University of Chicago, where it initially began, and during the COVID-19 pandemic, when the world went remote.
“We found that a lot of these developmental genes were just so great for development and for melanocyte stem cell maintenance also were really great at promoting melanoma,” Lang said, “so they’re the two sides of the same coin.”
The group’s research started with investigating a group of nine transcription factors called the “Pax” genes and ETS genes — a type of oncogenetic transcription — their role in progressing melanoma. Specifically, the PAX3 gene, which is found in the embryo and necessary for the melanocyte lineage — a process in which the skin cell grows excessively and can cause melanoma — is overexpressed in 99 percent of melanomas, Lang said.
“It’s something that the melanomas like to maintain,” Lang said, “and if you block PAX3, you lose the melanoma … but it’s very hard to target.”
To overcome the difficulties of targeting a specific gene, the researchers targeted the broader families of proteins affecting the genes, to indirectly prevent the growth of melanoma.
“If you can’t go get that guy, you go after his friends,” she said, “which is what we do in the paper.”
They found that the small molecule YK-4-279 “significantly inhibited cellular growth, invasion, and ETS factor function in melanoma cell lines,” the paper said.
The “concept of redundancy” was key to their findings, Lang said. She compared the method of targeting the protein family, many of which have the same general purpose in the progression of melanoma, to robbing a bank and taking out the bank’s security guards.
“You need to do something that takes care of all the guards at the same time,” Lang said. “That’s the general concept that we have in this paper, is that you don’t go after each one separately, you find something that gets them all targeted together.”
In terms of YK-4-279’s potential for use in melanoma treatment, Lang said the difference between this drug and other small molecule inhibitors used in treatment lies in what aspect of melanoma each targets.
“We think that this is targeting invasion and metastasis, so maybe they’ll be a good combination therapy,” she said. “It has potential for it, but it definitely needs to be tested.”
Some small molecule inhibitors developed in recent years have targeted BRAF, a gene critical for growth that occurs in about half of melanomas, Lang said, but treatments with these inhibitors typically do not keep melanoma at bay for prolonged periods of time.
“We see that this drug has potential, ” Lang said, “that it seems to be hitting different things than the [BRAF] inhibitor does.”
Lee Huang, a research assistant at BUSM and lead author on the paper, was the only member of the team able to go into the lab in person during lockdown to manage experiments.
As “essential lab personnel,” she was responsible for making sure all the lab operations were running smoothly.
“There’s a number of things in the lab that definitely need immediate attention sometimes,” Huang said. “Our CO2 and our liquid nitrogen, if they run out, we have to be there … so I was always there to check on it and while I was there, I’d also be doing experiments.”
Huang said she would come into contact with almost no one while working in the lab and commuting back and forth when the city and campus were still shut down.
“It was the most strange thing,” she said, “to go to and from the lab during the daytime and just not see anyone at all, for the whole day sometimes. So, I think that was the strangest thing about the pandemic.”
A group at George Washington University, Lang said, who initially discovered YK-4-279 are currently working on a clinical trial to use the drug in treatment for Ewing sarcoma.
“This is our motivation for pushing for this paper to get out,” Lang said. “There’s scientific glory and all that, but if this could help melanoma patients, that’s wonderful.”
