Oncology drives you to some pretty strange ideas about therapy. But that’s understandable – in what other field are you trying aggressively to kill off parts of the patient’s own body? That’s why chemotherapy started off with the study of people who had been exposed to mustard gas (during the Bari bombing raid), where it was noticed that systemic exposure to such brutally reactive compounds killed off fast-dividing cells before (just before) they killed off the rest.
We’ve come quite a ways since chemical warfare agents, although nitrogen mustards, never forget, are still in the pharmacopeia. There’s a new idea, though, will remind people of just that sort of desperation move. I was writing not long ago about glioblastoma and what an awful form of cancer it is, so it might not surprise you that it invites some of the wilder ideas for treatment. So, you’re looking for something that can reach in and kill off brain cells – not all of them, of course, just some of them – so what might you have seen recently that seems to go in and attack certain brain cell populations? Got it – how about Zika virus?
That’s the subject of this new paper from a multicenter team (Washington U, UCSD, Cleveland Clinic, University of Texas Medical Branch). (Here’s a press release). The terrible effects of Zika infection on a developing fetus are due to its effects on neuronal precursor cells, and it appears that the virus can attack the stem-cell-like population that’s such a problem with glioblastoma. One reason that this isn’t quite as crazy as it might sound is that glioblastoma tends to stay put – it’s very rarely metastatic, and after surgery (when that’s possible) it tends to recur in situ, from residual cells that can’t all be removed. So you don’t need to infect a patient’s whole body – just a localized shot of (attenuated) virus might do the trick.
And oncolytic viruses are, of course, not crazy either. There’s been a lot of work put into this general idea over the years, with recent hints of more success. There’s a virus approved for melanoma, although the jury’s still out on how effective it is, and several more in development. So Zika’s cellular targeting might be just the thing, and its effects in adults are notably less severe. (You do wonder, though, what the population of neuronal stem cells is like in the adult brain, whether wild-type Zika infections clear some of them out, and what the long-term effects of that might be). The mechanism by which Zika preferentially goes after these cells is unknown, but appears (as you might well imagine) to be based in different immune presentation by different cell populations.
The paper tries several patient-derived cell glioblastoma cell cultures and several strains of Zika virus, and it does seem to infect them readily, as opposed to differentiated glial cells, which are almost untouched. Experiments on tissue removed during glioblastoma surgical procedures (and control brain tissue removed during epilepsy surgery) confirmed these results. Related flaviviruses (like West Nile) don’t show this kind of selectivity. The authors went as far as mouse glioma models (and a mouse-adapted form of Zika) and demonstrated growth inhibition of the tumors, although this is arguably getting a bit far afield as compared to the results in human tissue.
The authors went on to use an attenuated form of the virus (with a mutation in its NS5 protein that inhibits replication) and showed that it still seemed effective (although wild-type was better) – and what’s more, the combination of it with the standard of care for glioblastoma, temozolimide, was additive. Their proposal is to keep working on the replication-crippled mutant virus to develop something that is worth taking into the clinic, and it should be noted that other viruses are being worked on for glioblastoma by other groups for the same end. Those are also eyebrow-raisers in some cases (polio!), but that’s how I started this post: oncology leads you to some pretty wild ideas. Good luck to all involved – glioblastoma is awful, and we need all the help we can get against it.