Hereās yet another one of those āMan, biology just will not stop piling on the multitaskingā examples. Everyone has heard of serotonin as a signaling molecule and neurotransmitter - itās one of the few that has name recognition even among people who donāt work in biomedicine at all.Ā But its effects in vivo are extremely varied and complex, not least because there are 13 subtypes of serotonin receptor stretched across six different families, with these occurring in a bewildering variety of different tissues (cardiovascular, the immune system, and many more). Itās a perfect example of evolution stumbling on a useful tool and then picking it up over and over again.
This new paper proposes, for example, that the serotonin reuptake inhibitors (SSRIs), which are famous as antidepressants among other uses, could have a role in cancer therapy. The reuptake pathway seems to inhibit CD8 T-cell antitumor immunity by keeping serotonin levels inside tumor tissue low (thereās that immune system connection just mentioned). And the paper shows that administration of SSRIs like fluoxetine (famous under the brand name Prozac) or citalopram (widely known as Celexa) at normal therapeutic doses in mouse cancer models significantly reduced tumor growth and improved survival across a range of different types (melanoma, colon, bladder, breast). Closer examination indicated that more active CD8 T cells appear to have been behind these effects. You might expect such a mode of action to synergize with anti-PD-1 immunooncology therapy, and so it proved: giving the SSRI drugs along with antibodies against mouse-type PD-1 showed even greater effects than either treatment alone.Ā
This would seem to be immediately actionable in clinical trials. One thing to keep in mind, though, is that the number of cancer patients who are already getting SSRIs is not insignificant, so that is going to have to be untangled along the way. Perhaps some of the benefit of that (and other) cancer treatments that weāve seen have been unexpectedly helped along a bit because we didnāt take this effect into account. And there are of course a lot of other potential mechanisms at work here, given the complexity of serotonin signaling in general. But it should be relatively straightforward to see if adding an SSRI to the treatment regimen patients getting anti-PD-1 cancer therapy improves their outcomes. And if it does, so much the better! These drugs are cheap and widely available.
There are plenty of other immune-modulating pathways that weāre just beginning to get a handle on (or are just beginning to realize that they exist at all). And thatās why I roll my eyes when I hear anyone say that they wonder if immuno-oncology is somehow āplayed outā. No, weāve just been messing around with the stuff that we know the most about and running variations on those. Itās going to be a long, long time before weāve exhausted the possibilities. If youāre looking for a boost to your companyās stock price by the second quarter of next year, then yeah, thatās tougher. But in the long term of the real world out here, there is just so, so much to do.