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Pathways to Discovery: Summer 2011

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Breakthroughs in Melanoma Research Stress Importance of Personalized Therapeutics

The science has been pushed to a very high level. We know a lot more about the details of melanoma’s biology than ever before.
Thomas Gajewski, MD, PhD

Advanced-stage melanoma is one of the deadliest cancers, with its patients rarely surviving more than a year after diagnosis. Researchers have long struggled to achieve substantial successful outcomes for this complex cancer, but in-depth analysis of its biology reveals that melanoma is not one cancer. It is a disease with many different subsets, each with unique molecular signatures.

Armed with this information, researchers can use molecular tests to identify mutations in specific genes and determine which patients are likely to benefit from therapy. Tailoring the therapy to each patient’s specific cancer is making melanoma the “unlikely poster child for personalized cancer therapy,” according to Thomas Gajewski, MD, PhD, professor of medicine and pathology.

“The science has been pushed to a very high level,” said Dr. Gajewski. “We know a lot more about the details of melanoma’s biology than ever before.” This information is helping researchers at UChicago and other institutions make significant advancements in melanoma treatment.

New Therapies
Immune therapy, which stimulates the body’s own immune defenses to eliminate cancer cells, is showing great promise for melanoma treatment. Scientists have identified a signaling pathway in the T cells of the immune system, called CTLA-4, that turns off the immune response against the melanoma, which, in turn, allows the tumor to grow and escape.

An antibody was developed to block CTLA-4 so that the T cells become reactivated and destroy the tumor. The generic name of the drug is ipilimumab, and it is the first melanoma therapy to show markedly improved survival in a Phase III clinical trial. Compared to the 6-month average survival rate for advanced melanoma, 40% of the patients in the trial were still alive at 1 year.

In about half of melanoma patients, a mutation in the B-Raf kinase, an enzyme that controls the transmission of information from the cell’s membrane to nucleus, causes it to be stuck “on” and drives the tumor to grow. A drug called PLX4032 was designed to block the B-Raf protein and has shown significant promise in Phase III randomized clinical trials and may soon become FDAapproved.

About 80% of patients with the B-Raf mutation respond to the drug, with their tumors rapidly shrinking. However, most patients have their tumors grow back, meaning the tumor somehow bypasses the block. Clinical trials are already under way to combine the B-Raf inhibitor with another drug that targets another enzyme in the same pathway.

The UChicago research team has participated in clinical trials for both of these therapies and continues to host clinical trials for investigational drugs to treat melanoma.

The Future Is Bright
Not only do these therapies show promise to effectively treat the deadly skin cancer, but Dr. Gajewski indicated that other types of cancer could potentially benefit from these discoveries. He predicts that the standard of practice for melanoma will soon involve routine screening of tumors for specific markers to match individual patients to the most appropriate treatment strategy.

Melanoma Risk Factors
Several risk factors may make you more likely to develop melanoma. They include:
■ UV radiation exposure from sunlight, tanning booths, and sunlamps
■ At least one severe, blistering sunburn
■ Fair skin, freckling, and light hair
■ Family history of melanoma
■ Previous melanoma
■ Moles
■ Immune suppression

Skin Cancer Prevention
■ Protect yourself and children from the sun.
■ Avoid tanning beds and sunlamps.
■ Check your skin regularly.
■ Have suspicious moles removed.
■ Consider genetic counseling and testing (if you have a family history of melanoma).