Advances in BRAF-Targeted Therapy for Metastatic Melanoma - Episode 2
Hussein A. Tawbi, MD: An oncogene-addicted cancer is a cancer that is driven almost entirely by 1 specific mutation and 1 specific gene. That’s really interesting because you know, in general, we know that cancers have a lot of mutations and those mutations can occur in various parts of the DNA. Sometimes they can affect the actual gene. Sometimes they don’t affect their function at all. And in very specific situations, a gene can be affected in a way that makes it very active—and becomes almost overactive and kind of goes into overdrive, so to speak—and really becomes so important that it drives the entire metabolism of the cancer cell. It drives the entire actually malignant phenotype of the cancer cell. It becomes so important to that cancer cell that if you by any chance manage to actually block it or stop its activity, that cancer cell actually dies, and that’s why we actually call it oncogene-addicted: because it basically takes over the entire cell. If you manage in some respects to be able to kind of counteract that, you actually can kill the cancer cell.
Ryan J. Sullivan, MD: An oncogene is a normal gene that is in all our cells, which are encoded by our DNA. However, in cancer it becomes activated. Typically it’s turned on by a mutation, which is a change in the DNA, which then will drive activation of that gene and a number of downstream consequences that typically lead to growth, survival, evasion of the immune system, recruitment of blood vessels, and a number of other features of a cell that’s dangerous to people.
In melanoma, we see a number of different oncogenes that can drive cancer. The most common is a gene called BRAF—RAF is actually the name of the gene, B is the subtype of the gene. But, BRAF is mutated in 40% to 50% of skin melanomas. Interestingly, melanoma is not always of the skin, so sometimes it’s on the skins of our palms and our soles and our nail beds; it’s slightly different. BRAF mutations are less common in that subtype. Sometimes, melanoma can rise out of the lining surfaces of our mouth or sinuses, or genitals, or guttural. BRAF mutations are less common in that situation too, about 10% of the time. And, sometimes, BRAF mutations can be of the eye structures. In the externalized structures, like the conjunctiva, BRAF mutations can happen 10% or 20% of the time. In the internal structures of the eye, like the retina, we don’t ever see BRAF mutations. So, it really is dependent on where the melanoma arises from to the most common oncogene, whether it’s present or not present and at what frequency.
Other common oncogenes that are mutated and thus activated include a gene called NRAS. NRAS is mutated about 20% to 25% of the time in skin melanoma, about 10% to 20% of the time in the skin melanoma of the palms, soles, and nail beds, and in the melanomas that arise off lining structure, so-called mucosal structures. But, they also are very rare in the eye, the melanomas that arise out of the eye, and can be seen on the external structures but are never seen on the internal structures.
Another mutation that we see is not really an oncogene but actually a tumor suppressor gene. Tumor suppressor genes are genes whose normal function is to prevent growth and survival in other types of processes that drive cancer. There’s a gene called NF1 that’s actually associated with an inherited condition called neurofibromatosis. When a mutation of that gene is inherited, it’s associated with a disease called neurofibromatosis. But, in the context of melanoma it can just become mutated. When it gets mutated, its function is lost. So, its regulatory control over cells is lost and thus can allow cancer to develop because it can’t suppress the tumor.
That’s present about 10% or 15% of the time in melanoma and is thought to be a driving oncogene in those tumors that are present, and you don’t have a BRAF mutation. You don’t have an NRAS mutation. For the rest of patients, we often can’t find a driving mutation. That’s true for probably about 20%, 25% of skin melanomas and about 50% of so-called mucosal melanomas.
In mucosal melanomas, we also see a different kind of oncogene called KIT. KIT is mutated probably between 15% and 25% of the time in those types of melanomas. And then we see mutations in genes called GNAQ and GNA11 in the internal eye melanomas.
All of those are potentially targetable. If you think about it, an oncogene which is upregulating and driving tumor growth is a vulnerability for a cancer cell. If we can just develop therapies that block that oncogene’s function, we probably can more effectively treat that cancer. There are a number of examples. The first, probably the most famous targeted therapy that was developed for cancer, was in a disease called CML: chronic myelogenous leukemia. There’s a very characteristic arrangement in the chromosomes that leads something called the Philadelphia chromosome, which activates a kinase called ABL.
Imatinib, which is otherwise known as Gleevec, is a potent inhibitor of ABL, and so the development of inhibitors that inhibit ABL were the first types of so-called targeted therapies for cancer that were developed. These drugs revolutionized the management of CNL, where uniformly, patients either died or had to undergo a bone marrow transplant within 3 or 4 years of diagnosis. Now, they are able to live pretty normal lives. That’s an extreme example of targeting oncogenes but a good one because it is still probably the prototype example of targeted therapy for an oncogene.
Transcript Edited for Clarity.