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U.S. Army grant advances UMMS studies targeting key melanoma protein

By Susan E.W. Spencer

UMass Medical School Communications

July 15, 2020
craig-ceol.jpg
Craig J. Ceol, PhD

The U.S. Department of Defense awarded a team of researchers led by Craig J. Ceol, PhD, assistant professor of molecular medicine, a $963,903 three-year grant to test potential approaches to killing metastatic melanoma tumors.

Malignant melanoma is the deadliest skin cancer, killing more than 7,200 Americans annually and 60,700 people worldwide. A majority of those who die from metastatic disease have tumors exhibiting resistance to one or more current therapies.

The project will use mouse xenografts and other preclinical approaches to examine the efficacy of targeting a cell-signaling mechanism, involving a protein called GDF6, discovered previously in Dr. Ceol’s lab as playing a primary role in metastatic melanoma.

Specifically, researchers will test whether antibodies targeting GDF6 can cause melanoma regression on their own or in combination with currently used therapies. They will also look at the importance of GDF6-dependent bone morphogenetic protein (BMP) signaling in rare melanoma subtypes: acral melanomas, found in areas that typically aren’t sun-damaged such as the bottom of the feet, and mucosal melanomas, found in surfaces such as the mouth.

“It’s a brand new target that could be important in a lot of patients,” Ceol said. “We have good preliminary data. We are aiming to get data that would support a clinical trial.”

Ceol explained that molecular signaling driven by GDF6 is active in nearly 80 percent of melanoma tumors and is required for melanoma cells to grow and survive. In patient samples, it is associated with metastatic progression and poor survival.

GDF6 functions normally in embryos to make pigment cells and promote bone growth. But it is not expressed in normal adult tissues, which makes it a good target because there is less likelihood of on-target toxicity, Ceol said. And because it exists outside the cell, it is accessible to antibodies.

Monoclonal antibodies created at UMMS that target GDF6 have been shown to kill melanoma cells in the lab.

The new grant enables Ceol’s lab to test in animal studies whether the antibodies made to target GDF6 work as a melanoma therapy, alone or with existing therapies.

Immunotherapies, which have come into use over the last five years, have been a big step forward from previous therapies such as small molecule inhibitors, but they still only work for 30 to 40 percent of patients with advanced melanoma, said Ceol.

One major obstacle to successful treatment has been drug resistance, which has been shown to occur in immunotherapies as well as with small molecule inhibitors targeting BRAF mutation, a big oncogene in melanoma.

“We’re looking to see whether GDF6 antibodies can complement those,” Ceol said. “One of the primary mechanisms of resistance could be dependent on GDF6, so we’re very interested in testing this possibility.”

The additional focus of the study—to examine GFD6’s role in rare acral and mucosal melanomas—is intended to illuminate a new potential pathway for treating these diseases, which are driven by different genes than common cutaneous melanoma. Ceol said, “The drugs that are normally used for cutaneous melanomas don’t really work well on acral melanomas and mucosal melanomas.”