Repurposing selective PDE5 inhibitors as anti-cancer agents

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Published: 5 Jun 2018
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Dr Pan Pantziarka - Anticancer Fund, Brussels, Belgium

Dr Pantziarka speaks with ecancer at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting about a recent paper, published in ecancermedicalscience, looking at repurposing selective PDE5 inhibitors as anti-cancer agents.

This latest paper is looking at the potential for repurposing the PDE5 inhibitors, so tadalafil, sildenafil and vardenafil. These are drugs which are already something of a repurposing success story in that they were developed for angina, that didn’t work, but then they were redeveloped for erectile dysfunction and they’ve been hugely successful for that. But these drugs have a number of effects which make them very interesting in an oncology context, particularly when it comes to their effects on the immune response. That makes them quite exciting drugs, especially as onco-immunology is a really big field and although there have been huge successes there, there’s a challenge to increase the number of patients who respond to these treatments and to extend the period of response. So these drugs may be quite interesting in that context.

What is it about their mechanism of action specifically?

The mechanism of action that’s particularly interesting with these drugs is that they seem to target populations of immune cells, particularly myeloid-derived suppressor cells which are implicated in protecting tumours from the immune system. Therefore, by targeting those the immune system gets a chance to attack the tumours. We’ve got evidence from a number of animal models where the effect is clearly shown only in animals with intact immune systems and not in mice that are immunocompromised.

Can you tell us about some of the key findings from this paper?

One of the interesting findings from this paper is that there is a huge amount of data that’s already there. It’s already being picked up by investigators so there are some very encouraging signs of clinical trial activity using these drugs. So, for example, in Canada there is a trial coming up called PERIOP 4 where they’re looking at adding a PDE5 inhibitor and an influenza vaccine at the time of surgery for gastrointestinal tumours, the idea being that the combination of the PDE5 inhibitor and a primer from a flu vaccine will encourage the immune system to kick in at the time of surgery and clear up any stray tumour cells that have escaped during surgery. So that’s a very interesting, very novel approach to explore in a clinical trial.

Yes, I was just about to ask with the action on myelosuppression cells it seems like a combination therapy would be a key avenue for bringing these to the fore.

Yes. Although there’s some evidence that there are other mechanisms of activity, so it targets tumour hypoxia, in some sensitive cell types it’s pro-apoptotic, it does seem that the immune response is the key finding. But on its own it’s not enough, it needs to be combined with chemotherapy or a checkpoint inhibition or some other mechanism. So these drugs are definitely add-ons to existing treatments rather than novel treatments for monotherapy.

You mentioned earlier how this has gone from treatments for angina through to erectile dysfunction and now this repurposing. Is there any common link between the repurposing targets which you’ve discussed with ecancer before?

This is the ninth paper that we’ve published with ecancer looking at different drugs. One of the interesting things about these is that all of these drugs have been developed across very different disease areas but they have multiple targets, multiple mechanisms of actions. So in contrast to the way drugs are developed now where you have one specific molecular target, these drugs seem to have multiple targets so we should start thinking of these as multi-targeted therapies which can attack relevant pathways that are common across different cancer types. Very few of these drugs are specific to one tissue type or one cancer type.

Does that multi-target activity, it does them some service in their now intended use, but does that open up any possible conflicts of action if they are used in combination with other chemotherapy agents or immune therapies?

Obviously whenever you’re combining drugs there’s a question of how they interact. One of the issues for the clinical trials is although we know these drugs are very safe so we can skip the phase I trials to establish that they’re safe on their own, we need to run additional trials sometimes to check are there interactions with the standard treatments in a number of cancers? But that still means that we can take advantage of what we know about the dosing, the mechanisms of action, the side effect profile. So that still puts us ahead of where we would be with a de novo molecule that’s just been developed in the lab.

Can you think of anything else about the paper or your experience in repurposing to mention now?

What’s interesting is we’ve been partnering with ecancer for quite a while now developing these papers and in the beginning repurposing was seen as something a little bit left-field, not quite part of the mainstream. Yet we’ve seen at ASCO results of trials using metformin, repurposing is on the agenda across different cancer types, so it has been a really positive growth in the last few years of interest in drug repurposing. Working with ecancer has definitely helped raise that profile.