Shutting Down Pathways That Help Melanoma Spread

Nearly 10,000 adults in the United States are expected to die this year from melanoma, the most aggressive type of skin cancer. Melanoma can be cured if caught early, but if found in later stages, when it has already spread to other parts of the body, it can be very difficult to treat.

In recent years, targeted drugs and immunotherapies have become available, and in some cases, make a difference for patients with metastatic melanoma. About 50% of melanoma patients have a problem with a gene called BRAF, which can now be treated with targeted drugs. The use of these drugs has been among “the most revolutionary [in metastatic melanoma] because they are allowing people to live longer,” says Barbara Bedogni, Ph.D., an American Cancer Society-funded researcher at Case Western Reserve University. “But most people eventually develop new melanomas that are no longer responsive to these targeted therapies.”

close up portrait of Barbara Bedogni, PhD, Case Western Reserve University

Barbara Bedogni, Ph.D., a researcher at Case Western Reserve University, is looking for ways to help metastatic melanoma patients.

To overcome this problem, Bedogni and her team are working on targeting molecules that they recently discovered are not working properly in melanomas. Bedogni has found that two proteins – called Notch1 and neuregulin1 – play a fundamental role in the growth and spread of melanoma cells. She hopes to find out whether blocking the activity of these two molecules can stop melanoma growth and metastasis.

Images from Dr. Barbara Bedogni’s lab of samples of melanoma tissue, with varying levels of the protein Notch1, which Bedogni believes plays a role in the growth and spread of melanoma cells. The samples, from left to right, show increasing levels of Notch 1.

Images from Dr. Bedogni’s lab of samples of melanoma tissue, with varying levels of the protein Notch1, which Bedogni believes plays a role in the growth and spread of melanoma cells. The samples, from left to right, show increasing levels of Notch 1.

Bedogni’s experiments thus far show that targeting Notch1 and the gene that neuregulin1 controls (called ERBB3) may be a treatment strategy that could apply to most patients with metastatic melanoma. “What we see is in about 60% to 70% of the samples we tested, these molecules are very active,” says Bedogni. Additionally, Bedogni has found that melanomas with a BRAF mutation as well as those without the mutation have issues with the functioning of Notch1 and neuregulin1, meaning it might be possible to combine treatments that attack both problems. “The hope is to create a therapy that can target these 60% to 70% of patients.”

The good news is that drugs that inhibit both Notch1 and ERBB3 already exist and are used for the treatment of other cancers, meaning such drugs may be more easily available for use against melanoma. Bedogni is testing these existing therapies for use against Notch1 and ERBB3, and is also trying to create new, better inhibitors as well. If the existing drugs Bedogni is working on prove effective, she thinks that the treatment could be tested in a clinical trial in a year or two.

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