I know I post a lot of stories about immunotherapy. The potential for that type of treatment could revolutionize how we fight melanoma. But a new study caught my eye and it’s definitely an intriguing avenue of research.
Some melanoma tumors arise from a mutation in the BRAF gene, most common type being the V600E (but there are other mutation types). BRAF-mutated melanoma is actually pretty distinct from BRAF Wild Type-melanoma from a clinical perspective: the patients usually present younger in age; have superficial spreading or nodular melanoma; is a more aggressive form; tumors usually are in areas that aren’t normally chronically exposed to sun damage; and usually metastasizes to the brain. The discovery of the BRAF mutation led to the development and use of BRAF and MEK inhibitors, often used in combination therapy, to prolong survival rates. Drugs like dabrafenib, trametinib, vemurafenib and cobimetinib have literally given years back to some melanoma patients.
But in some instances, the cancer cells become resistant to these life-prolonging drugs. Previous research determined that resistant cancer stem cells produce an enzyme called aldehyde dehydrogenase 1 (ALDH1A1) at higher than normal levels. (By the way, cells in various other forms of cancer, not just melanoma, also produce this enzyme and/or ALDH1A3. The other ALDH enzyme is involved in breaking down alcohol in the human body (ALDH2). They’re different despite the very similar sounding name; so inhibitors for that enzyme won’t be effective against the ones produced by cancer cells.) Anyway, because of this propensity of these cells to produce ALDH1, some scientists are investigating ways to either block the production of that enzyme or kill the cells that produce it at high levels.
Researchers at the University of Edinburgh’s Medical Research Council Institute of Genetics and Molecular Medicine took a look at an antibiotic called nifuroxazide. It’s been around since the 1960s and is typically used to treat colitis and diarrhea. It’s in a class of drugs known as 5-nitrofuran pro-drugs or 5-NFNs. Previous studies have shown that this class of drugs may have anti-cancer properties, albeit the exact mechanism wasn’t understood.
First, the U.K. team tested the effect nifuroxazide had on melanoma cells in molecular assays and when it looked like there was something interesting going on, they then grew melanoma cells and dosed them with the antibiotic. They found that cells with high levels of ALDH1 grew in colonies (i.e. tumors) and were very susceptible to nifuroxazide; while cells that produced low levels of the enzyme weren’t really affected by the antibiotic. Once those studies were carried out, they then grafted human melanoma onto mice and treated the mice with nifuroxazide. And once again, the nifuroxazide-treated melanoma growth halted and in some cases, regressed. Analyzing the tumors after treatment, they noted that “nifuroxazide does not just inhibit ALDH enzyme activity in cells, but specifically eradicates ALDH1High tumor subpopulations.” Even more interesting? They took those same tumors and tried to re-establish melanoma (kinda of like initiating a recurrence of the cancer) and found that the tumors treated with nifuroxazide wouldn’t take hold again.
Ok, so nifuroxazide seems to eliminate cells that produce high levels of ALDH1, in theory killing cancer cells or at least causing them not to continue to multiple. But what about that BRAF resistance thing I was talking about earlier? The researchers took a look at ALDH1 antibodies in seven human melanoma patients that exhibited BRAF and MEK inhibitor resistance. As you might expect, the tests showed there was pretty significant levels of ALDH1 in four of those patients. Meaning that this finding indicates that ALDH1 may be a reason for the relapse of melanoma.
By looking at the effect of BRAF and MEK inhibitor drugs had on these cells, researchers discovered that vemurafenib (BRAFi) plus trametinib (MEKi) actually increased the production of ALDH1 levels AND the sensitivity to nifuroxazide. While the ability of the cancer cells to react with increased production of the bad enzyme is not good in normal circumstances, by adding nifuroxazide to the mix, it’s like the cancer cells are shining a huge light saying “here I am, come get me and neutralize me”.
Now obviously, more research needs to be done in human patients to see if the effects noted in animal models and molecular studies translate over. But it’s another step in figuring out the mechanism behind why certain patients develop BRAF and MEK inhibitor resistance and how to develop treatments that surmount it.