Dr. Warrick Bishop: Welcome, my name is Dr.

Warrick Bishop. I'm a cardiologist, an author, and a keynote speaker. I'm the CEO of the Healthy Heart Network.

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Hi, this is an interesting one.

If you've ever come across the situation where you know of someone who is being told they're cured of cancer, and then sometime later—five years, ten years, twenty years—exactly the same cancer comes back, how does it happen? We know it happens. We see it.

We know people that that's happened to, or we will know of people that.

Welcome to my podcast and videocast station. Thank you for joining me.

I really do appreciate your time. Today, I'm going to be talking about this late recurrence of cancer. So if you're interested, stay tuned.

I'm going to share my screen so that if you're watching this on YouTube, that's fantastic. You'll see a few slides. If you're listening to this as a podcast, that's fine too.

Truth be told, you will still get all the gist of it, 'cause I will endeavor to basically describe all the details so that you can listen and not miss out.

So, we're talking about cancer recurrence. What actually is going on, and why do cancers seem to come back after years or even decades of what's said to be successful treatment?

I think this is a really important space.

What we sort of realize is that there's this phase that some cancer cells go into called a dormant state or quiescence. And that's not forever.

It turns out that early and late-stage cancer cells can enter this dormant state and end up in distant tissue, perhaps bone marrow or lung—it doesn't matter. This can be long before any recurrence is ever diagnosed. These can only be handfuls of cells; they don't need to be a lot.

They are alive, but they're not super active, and they can live in tissues where they're supported. But they're in this sort of quiet, hibernation state, if you like, this quiescent state.

Because they're so quiet, a lot of our techniques for evaluating the presence of cancer just don't work.

We often use techniques that are designed to show us active cells—cells that are gobbling up lots of energy. And these particular cells are not. They're just "quiet," resting, hibernating, quiescent or dormant, and they're sitting in tissues remote from where the cancer originally started.

Dormant cells also try to keep themselves alive. They're actually a little bit cunning that way, and they switch on survival tools such as metabolic adaptation, allowing them to persist and remain alive for long periods of time in a low oxygen, low nutrient environment. It seems that there's signaling that turns these tumors on, and a thing called "integrin," which is a cell marker, particularly activation of "integrin beta1," appears to help cells exit that quiescent, hibernation dormancy state and resume growth.

So, there are local triggers that will turn those cells back on.

Those cells have avoided detection and eradication because they seem to avoid the immune system and often can be in the setting of immune suppression. Aging is associated with immune suppression, chronic inflammation, psychological stress, and even some anti-cancer therapies themselves can diminish the immune surveillance that our own bodies would have to keep these dormant cells in check.

Complicated, isn't it?

There can also be changes in the surrounding tissue structure that may mean new blood vessels grow into a particular region, and that may actually help reactivate resting cells. So, I guess the thing that's worth thinking about here is that these dormant cells, these hibernating quiet cells, can slip past our best diagnostic tools for trying to find them.

It's because they're not dividing; they're not metabolically active. Because of that, they're hard to detect because a lot of our markers rely on those cells being metabolically active. But they are also fairly resistant to chemotherapy and radiation because chemotherapy and radiation really work best in the cells that are metabolically active and turning over.

If the cells are sitting there quietly and they're irradiated or exposed to chemo, then they may not be damaged at all, so they can hang around. Their small numbers and low metabolic activity can make them really, really difficult to identify. Certainly, if you can't identify them, you can't biopsy them and even know they're there.

They do hang out in very tricky specialized tissues such as bone marrow, and in those locations, they can therefore be shielded from the body's efforts to identify them. Some standard chemotherapeutic agents may actually promote this process of dormancy. Agents such as doxorubicin, cisplatin, and the taxanes may actually be involved in driving that response for some particular cancers.

So what can we do about it? Well, it's a space where science and medicine are advancing. There are efforts to try and detect better, contain these cells, or even eliminate them.

In the process of trying to detect them, research is looking at peptide-based molecular probes that may attach to these particular dormant cells and act as markers for imaging. What I mean is that if you can find a marker that's got a nuclear attachment to it, if that marker then sits on and clusters on a group of these cells, then when you use a scanner to measure for nuclear radiation or nuclear emission from these cells, peptides with a tracer on, the fluorescent tracer on, then it should show up. Think of a PET scan using a fluorescent glucose molecule to show where metabolic cancer cells are.

There's also a line of investigation looking at trying to keep these cells asleep. So if they're asleep and they're remote somewhere, why don't we just keep them asleep? Because they're not causing any problems.

There are agents such as 5-azacytidine and all-trans retinoic acid, which can potentially be advantageous at keeping these cells asleep. If you keep them asleep, they don't divide, and they won't come back as a recurrence of that cancer.

There are also mechanisms looking at trying to eliminate these cells.

This is using autophagy inhibitors combined with things like mTOR inhibitors or bone marrow targeting drugs, and even personalized vaccines that can be built around a patient's own individual tumor markers. Really interesting space, particularly since there's been a demonstration of mRNA vaccines against particular tumors reducing recurrence or death by up to almost 50%—49%, which is amazing. This is using markers directed to the actual cancer cell, using those markers to then find the dormant cells with the same cellular signature and identifying them that way.

Well, what is the takeaway with this particular late recurrence of cancer? It's often driven by these dormant cells which have survived treatment and settled somewhere distant—often not in large numbers. It's often linked to the immune system dropping off, aging, chronic inflammation, and stress, all driving that.

There are some new detection tools, and there are drugs that may help us stabilize that. We're looking at personalized vaccines, which will be an incredible step to really close that gap.

If you're a cancer survivor, what does it mean for you?

Well, have a chat with your oncologist, particularly about your own long-term survival and surveillance plan, and whether any of these particular modalities that are on the near horizon might be relevant for you.

I think that's a fascinating space; I really do. And we haven't even touched on the role of considering prolonged fasting for those particular cells.

I'm not sure how that fits in, but we do know that at around 48 hours, many cancer cells will be under a lot of stress and strain from fasting, and that may be one way to actually help support clearing those cells.

I hope you found this presentation interesting. If you have or know someone that it might be valuable for, please share it with them.

I do put a lot of work into these, and I would love people to get the value that I try to put into it out of it. I always appreciate your time, so if you've gotten this far, I really do appreciate you listening this long.

Thank you.

I will be talking about CT radiation risk exposure sometime soon. I'm not sure exactly what order it'll be in, but if you are interested in CT radiation risk exposure, if you had a few CTs, tune in for that. That'll be really useful.

For now, though, I am going to wish you the very best. I do hope you live as well as possible for as long as possible. Take care and bye for now.

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