Reporting in the June issue of Cancer Cell, the scientists showed that a small transcription factor family, made up of several proteins that control the activity of key growth genes, functions abnormally in malignant melanoma, two forms of soft-tissue sarcomas, and a type of kidney cancer that mainly affects children. Still other cancers sharing the same causative mechanism may yet be found, the scientists said.
"One would have never thought of grouping these tumors together," said David E. Fisher, MD, PhD, a pediatric oncologist at Dana-Farber and Children's Hospital Boston, who is senior author of the paper. The lead author is Ian J. Davis, MD, PhD, of Dana-Farber and Children's Hospital Boston.
"The importance of this finding is that it suggests a common 'engine' is driving these seemingly unrelated cancers," Fisher said. "Therefore, it is plausible that common therapeutic strategies might be applied to the tumors as well." The newly grouped cancers ?melanoma, clear cell sarcoma, alveolar soft part sarcoma, and pediatric renal carcinoma ?are often lethal if surgery cannot completely remove them.
Dana-Farber researchers are already using these new insights in clinical trials of a cancer vaccine, GVAX, that previously has produced rare but dramatic responses in some patients with advanced melanoma. "We have just opened a trial to offer the same vaccine to patients with all of the other cancers in this related family," said Fisher. "Prior to this, virtually no rational experimental treatments were available for these diseases, and patients have already started coming from throughout the country to enlist in our trial."
The transcription factor family is collectively known as MiT. Its kingpin, a protein called MITF, is needed by the body to develop normally functioning melanocytes, the pigment-producing cells of the skin and hair. Mutations that disable MITF cause lack of pigment, as in albinism, but when the gene for MITF is amplified ?too many copies in a cell ?it can cause melanoma, because the growth genes that are regulated by MITF act like a stuck "on" switch for cell proliferation. Last year, investigators based at Dana-Farber (including Fisher and his colleagues) reported that the MITF gene is amplified in 20 percent of melanoma tumors.
In addition, Fisher and Scott R. Granter, MD, of Children's Hospital Boston ?also an author of the Cancer Cell article ?previously found that MITF was present in a dangerous type of soft-tissue tumor ?clear cell sarcoma ?that develops near muscles and tendons in teenagers and young adults. The scientists had been alerted to the possibility of MITF involvement because clear cell sarcoma tumors are sometimes pigmented ?a process requiring the MITF transcription factor. In this form of sarcoma, Fisher explained, the MITF gene is overactivated by an abnormal joining, or fusion, of two other genes. MITF, in turn, is directly responsible for malignant growth and survival of the cells. Suppression of MITF by genetic means in the laboratory is lethal to clear cell sarcoma.
While no drug currently exists to directly suppress MITF, the identification of MITF's role opens a door to potential therapies because the researchers have identified some of the genes and proteins that MITF regulates that new drugs could be used to block. One of the targets is Bcl-2, which enables cancer cells to survive when the body has ordered them to self-destruct, and another is CDK-2, a protein that is often abnormal in cancer.
Related to MITF in the MiT transcription factor family are three proteins named TFEB, TFE3, and TFEC. One of them, TFEB, is known to be abnormal in certain kidney carcinomas in children, and TFE3 is involved in another rare soft-tissue tumor, alveolar soft part sarcoma, which tends to affect female children and young adults.
"It is now apparent that all of these tumors share this central family of oncogenes that are functionally interchangeable," said Fisher, who is also a professor of pediatrics at Harvard Medical School. His team demonstrated this point by showing that when tumors in mice were shrunk by disabling one of the transcription factors, replacing it with another member of the family re-started the tumor's growth.In the short term, clinicians will attempt to exploit this interconnectedness by using therapies that may be effective against one tumor to try to treat other tumors, said Fisher. "In the longer term, the focus is on targeting the real culprit ?and that is the MiT transcription factors or their targets. There is lots of excitement, and I believe that is the way to really nail these tumors."