Everyone keeping up with the news will have heard about Sen. McCain’s diagnosis of glioblastoma multiforme (GBM). This is not good news at all; GBM is a very aggressive tumor type for which treatment options are poor. The contrast to ex-President Jimmy Carter’s brain cancer experience is stark, and many people outside the biomedical field must be wondering why the two are so different.
Carter’s diagnosis was metastatic melanoma, which until very recently was just about as bad an answer to get as GBM. Surgery and radiation have been the standard combination for melanoma, but the metastatic form of the disease is much harder to deal with, since it has, of course, spread to other organs at that point. But immunotherapy has been added to that in recent years, and that’s what tipped the balance in President Carter’s case. Many metastatic melanomas are particularly dependent on PD-1 as a mechanism to keep T cells from recognizing and attacking them, and the antibodies targeting that protein have shown themselves to be quite effective. Unfortunately, GBM is another thing entirely, and illustrates the problem that cancer is really a collection of thousands of different diseases.
Glioblastomas are characterized by extreme genomic instability, even by the standards of cancer cells, meaning that what appears to be a single tumor is almost certainly a large collection of different cell types using different mechanisms to grow and survive. That explains why no single therapy has had much success in the field. The standard treatment is temolozomide, which is really a brain-penetrating prodrug that produces the same species as another chemotherapy agent, dacarbazine. That’s a DNA alkylating agent, so we’re now back into the classic (and brutal) form of chemotherapy, where you’re damaging dividing cells in general, but damaging the rapidly dividing ones even more (dacarbazine is, in fact, used to treat metastatic melanoma as well). It’s also a prodrug itself, and organic chemists will be alarmed to find out that it breaks down to diazomethane, which is what does the actual methylation of guanine bases in DNA. Cancer therapy with a systemically dosed diazomethane precursor sounds pretty primitive, and it is. But that’s the best we have for GBM.
Many attempts have been made at improving this situation, and one of the most notable was the idea of placing slowly dissolving wafers containing the chemotherapy agent carmustine at the site of the tumor directly after surgical resection. This makes a lot of sense, as the recurrence of GBM after surgery makes it clear that it’s impossible to do a clean-margin removal of the cancer tissue. Carmustine is a really rough compound, a combination of a nitrogen mustard and a nitrosourea (which is a diazomethane precursor, as those who have made the reagent in the lab well know). Unfortunately, the wafer (brand name Gliadel) has not seemed to demonstrate any advantage in survival compared to regular temozolomide treatment, at least not in randomized trials (cohort studies have looked better). So it’s not clear if there’s a real advantage in using it.
As you would figure, all sorts of approaches have been tried against GBM, with a conspicuous lack of success. One that remains to be tested is the use of a GSK3 kinase inhibitor along with radiation, which has shown promise in model studies. Let’s hope that this translates into efficacy in humans, because something efficacious is badly needed in this field. It’s a really tough one.