Researchers at Dana-Farber Cancer Institute report that a common "oncogene engine" – a small family of malfunctioning cell growth switches – drives several seemingly unrelated, lethal forms of cancer, including malignant melanoma. The finding suggests that it may be possible to attack these different cancers with the same therapy.
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."
Janet Haley Dubow | EurekAlert!
A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to developing a new active ingredient against chronic infections
21.08.2017 | Deutsches Zentrum für Infektionsforschung
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
21.08.2017 | Materials Sciences
21.08.2017 | Health and Medicine
21.08.2017 | Materials Sciences