Thursday, June 2, 2011

Target: Melanoma

The latest news on melanoma treatment and research

Dr.  Tsao

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Broadway producer Debra Black was diagnosed with stage II melanoma more than four years ago. Although her treatment was physically and emotionally difficult, she counts herself as one of the lucky ones because her disease was treatable. Historically, most patients with advanced-stage melanoma face a grim prognosis. Today, however, a targeted therapy called PLX4032 is extending the lives of patients battling this disease.

Approximately half of all patients with advanced melanoma have a mutation in the BRAF gene, which produces a protein vital to normal cell growth. This mutation is acquired or spontaneous, not inherited, and is present only in cancerous cells. Ordinarily the gene switches on and off in response to the body’s needs but, when mutated, the gene is permanently on, over-producing a protein that leads to unchecked cell growth. PLX4032 attaches to the defective protein, stopping its destructive behavior. Two clinical trials of the drug by Keith Flaherty, MD, director of developmental therapeutics for the Massachusetts General Hospital Cancer Center, produced astounding results: More than half of the patients receiving the medication experienced a shrinkage or disappearance of their tumors. Patients lived an average of seven months without progression of their disease, a phenomenal extension in a group of patients who experience, on average, only a two-month reprieve with chemotherapy.

“This response is gratifying,” says Flaherty, “especially when you consider that as many as 90 percent of patients with this mutation have a positive response early in their treatment, and that traditional chemotherapies gave us only a 10 percent response. But there is still work to be done.”

Flaherty and other melanoma specialists at the Mass General Cancer Center are probing the same questions that face clinical researchers investigating other targeted therapies: What’s different in the patients who have the mutation but do not respond to PLX4032? How can doctors know up front who will respond, so they can direct them to the right treatment? And what about the patients with advanced melanoma and no BRAF mutation?

For Flaherty, ongoing work to answer these questions includes a next generation clinical trial that combines a BRAF inhibitor with another drug that blocks a different component of the same pathway. This approach has been validated in human melanoma cells in the laboratory and is now being offered to patients with advanced melanoma at the Mass General Cancer Center and other locations. Flaherty is also readying a clinical trial of a BRAF inhibitor and an inhibitor of a secondary pathway believed important in melanoma. “These types of combinations,” he says, “will potentially help responses last longer.” Mass General Surgical Oncologist Jennifer Wargo, MD, is taking a different approach against BRAF-mutated melanomas, proposing to unite targeted agents with immunotherapy. Immunotherapy has, for the past decades, been the most effective weapon in the anti- melanoma arsenal. It works by revving up immune cells, called T cells, to fight the disease. One FDA-approved form of immunotherapy for metastatic melanoma, interleukin-2 (IL2), leads to a complete regression of disease in eight percent of patients. In another 15 percent of patients, IL2 causes some shrinkage or disappearance of disease. A second form of immunotherapy available to Mass General Cancer Center patients through clinical trials, ipilimumab, has been recently approved by the FDA for use in patients with advanced melanoma because of its ability to produce long-lasting responses.

In conjunction with Mass General Cancer Center colleagues, Wargo has performed pre-clinical studies that provide solid evidence that combining BRAF-targeted therapy and immunotherapy may significantly improve responses. “The BRAF mutation appears to allow melanomas to essentially hide from the immune system,” she says. “Our work shows that BRAF inhibitors improve the ability of T cells to recognize and kill melanoma cells.” Her proposal to combine PLX4032 with immunotherapy, either ipilimumab or IL2, is intended to merge the benefits of both therapeutic approaches, increasing the likelihood of permanent disease regression in patients with BRAF mutations.

The excitement over BRAF inhibitors extends beyond melanoma. Because BRAF mutations are present in other cancers, clinical researchers at the Mass General Cancer Center are extending knowledge of BRAF-inhibitors to patients with cancers other than melanoma. “The idea is that we can treat cancer based on its genetic fingerprint no matter where it originally arose,” says Donald Lawrence, MD, clinical director of the Mass General Cancer Center Melanoma Program. Lawrence is leading a multi-center clinical trial using BRAF-inhibitors in patients with lung, colon, thyroid, ovarian or other cancers that are positive for the BRAF mutation.

Targeted therapies are also being combined with the other standard melanoma treatment approaches, surgery and radiation, to improve care at all stages of disease. Kenneth Tanabe, MD, chief of the Division of Surgical Oncology and deputy clinical director of the Mass General Cancer Center, says that “It will be interesting to see if these agents are beneficial in increasing the number of patients who are cured with surgery,” the first line of defense for melanoma. Mutation status, along with other microscopic features of tumors, also helps multidisciplinary teams determine how aggressively a tumor needs to be treated. Characteristics associated with low rates of metastasis or better outcomes, for example, could tell surgeons that lesions can be safely removed with smaller margins between cancerous and healthy tissue, thus reducing scarring.

These advances are exciting for people affected by melanoma as well as for doctors and researchers. They are particularly gratifying for Debra Black, whose diagnosis made her recognize the scarcity of effective treatments for advanced melanoma. In conjunction with her husband, Leon Black, she decided to accelerate progress toward a cure. Working with Michael Milken, who established the Prostate Cancer Foundation in 1993, and the Milken Institute, the Blacks founded the Melanoma Research Alliance (MRA). Since its inception in 2007, MRA has provided more than $22 million for research in melanoma prevention, diagnosis and treatment. Last year, MRA honored Flaherty; David Fisher, MD, PhD, chief of the Mass General Dermatology Service, director of the Melanoma Program in the Mass General Cancer Center, and director of the Cutaneous Biology Research Center; Hensin Tsao, MD, PhD, clinical director of the Mass General Melanoma and Pigmented Lesion Center, and director of the Mass General Melanoma Genetics Program; and colleagues at other academic melanoma centers with a $2 million award, one of the largest grants given to date by the MRA. The investigators will establish a consortium of cancer centers that have led clinical trials of PLX4032 to share information and conduct studies aimed at overcoming resistance to BRAF targeted therapies and developing new melanoma treatments. Milken’s Prostate Cancer Foundation has contributed generously to cancer research at the Mass General Cancer Center, including the work of Matthew Smith, MD, PhD, director of the Genitourinary Malignancies Program.

“BRAF inhibitors are a wonderful breakthrough, but the effect is temporary,” says Debra Black. “Studies like the ones underway at the Mass General Cancer Center are our greatest hope.”

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