Stephen Hodi, MD
In a demonstration that even some of the most hard-to-treat tumors
may one day succumb to therapies aimed at molecular "weak points,"
researchers at Dana-Farber Cancer Institute report the first instance in
which metastatic melanoma has been driven into remission by a targeted
The report, published in the April 20 issue of the Journal of Clinical Oncology,
describes the case of a 79-year-old woman with melanoma tumors in
several parts of her abdomen. When lab tests showed the tumor cells
carried an abnormality in a gene called KIT, the patient enrolled in a clinical trial involving Gleevec® (Imatinib), a drug known to target that gene.
Four weeks after beginning therapy, imaging exams showed a dramatic
reduction in tumor size and metabolism: two of the tumor masses had
disappeared and several others had shrunken considerably. Four months
later, the tumors were still in check, and today, nine months after the
start of therapy, she continues to take the drug and her condition
"This is the first proof of principle that we can find an Achilles'
heel in melanoma" — a gene critical to tumor cell growth and
proliferation — "and, by targeting that gene with a drug, cause the cell
to die," says the study's lead author, Stephen Hodi, MD, of
Dana-Farber. "It is especially exciting because there haven't been any
effective treatments for melanoma patients with metastatic disease."
Although the report involves just one patient, it should inject new
confidence in the fight against melanoma, Hodi says. Because previous
research has failed to find any genetic Achilles' heels capable of
shutting down melanoma cell growth, some researchers had speculated that
none may exist for such cells. The discovery of one suggests there may
KIT mutations are found in only a small percentage of
melanomas, so Imatinib does not represent a universal treatment for the
disease, Hodi explains. Recent studies have found KIT mutations
in 11 percent of acral melanomas (which arise in skin without hair
follicles, such as that of the palms, foot soles, and nail beds, and
account for 5 percent of all melanomas), 21 percent of mucosal melanomas
(which arise in the mucous membranes of some organs), and 17 percent of
melanomas arising in chronically sun-damaged skin. For patients with
these conditions, particularly those who carry a mutation in a
particular section of the gene, Imatinib may well prove beneficial.
Imatinib's effectiveness against tumors with KIT mutations
was first demonstrated in gastrointestinal stromal tumors (GISTs), a
relatively rare malignancy of the digestive tract. An estimated 75-80
percent of GISTs have KIT mutations, and Imatinib has caused
such tumors to stabilize or retreat in 75-90 percent of patients
receiving it. In most of these patients, however, tumors eventually
begin growing again as they become resistant to the drug.
The KIT mutation in the patient described in the study
involved a protein-coding section of the gene where DNA was duplicated.
This section, known as the "juxtamembrane domain," is the most frequent
site of mutation in GIST, and is associated with a strong tumor response
"Dramatic remissions in metastatic melanoma are something that, as
physicians, we've rarely seen," Hodi remarks. "Confirming these results
will require enrolling additional patients in clinical trials —
something we're actively working to accomplish."
The senior author of the study is David E. Fisher, MD, PhD, who
participated in the research as a Dana-Farber faculty member and is now
at Massachusetts General Hospital. Other co-authors include Philip
Friedlander, MD, PhD, Annick D. Van den Abbeele, MD, George Demetri, MD,
Suzanne Mac Rae, MPH, Andrea Kruse, and Jyothi Jagannathan, MD, of
Dana-Farber; Christopher Corless, MD, PhD, and Michael Heinrich, MD, of
Oregon Health & Science University; and Elsa Velazquez, MD, of
Brigham and Women's Hospital.
Funding for the research was provided in part by the Ron Gelb Melanoma Research Fund at Dana-Farber.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National