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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, 10 years, 20 years, exactly the same cancer comes back, how does that happen? And we know it happens. We see it. We will know people that that's happened to, or we will know of people who know people who will tell those stories. My name is Dr. Warrick Bishop. 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 because 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 it's a really important space. So 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 in a cancer story, in a cancer situation, that some tumor cells can disseminate or leave the primary cancer tissue and end up in distant tissue, perhaps bone marrow, lung, doesn't matter. And this can be long before any recurrence is ever diagnosed. And these can only be handfuls of cells, actually. 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 sort of state, if you like, this quiescent state. And because they're so quiet, a lot of our techniques for evaluating presence of cancer just don't work because we often use techniques that are designed to show us active cells, cells that are gobbling up lots of energy. And these cells in particular are not. They're just quiet, resting, hibernating, quiescent or dormant. And they're sitting in tissues remote to where the cancer originally started. These 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 a signaling that turns these tumors on. And a thing called integrin, which is a salient marker, particularly activation of integrin beta-1, appears to help cells exit that quiescent, that hibernation dormancy state and resume growth. So there's 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. So aging is associated with immune suppression, chronic inflammation, psychological stress, even some anti-cancer therapies themselves will 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 that 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. And because of that, they're hard to detect because a lot of our markers are reliant on those cells being metabolically active. But they're also fairly resistant to chemotherapy and radiation because chemotherapy and radiation really work best in the cells that are metabolically active and turning over because the chemo and radiation smash that process. But if the cell's sitting there quietly and it's irradiated or it's exposed to chemo, then the cell may not be that damaged at all. So they can hang around. There's small numbers and their low metabolic activity can make them really, really difficult to identify. And 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 can therefore be shielded from the body's efforts to identify them. And some standard chemotherapeutic agents may actually promote this process of dormancy, this hibernation. 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 is advancing. There is or there are efforts to try and detect better, contain these cells or even eliminate them. And in the process of trying to detect them, the research is looking at peptide-based molecular probes that may attach to these particular dormant cells and act as the marker for imaging. So what I'm meaning 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 peptides with the tracer on, the fluorescent tracer on, then it should show up. Think of a PET scan using sort of a fluorescent glucose molecule to show up 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. So there are AGs such as 5-azacitidine and TRAN and all TRANS, retinoic acid, which can potentially be advantageous at keeping these cells asleep. And if you're keeping them asleep, they don't divide, they won't come back as a recurrence of that cancer. And there's also mechanisms looking at trying to eliminate these cells. And 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 has been demonstration of mRNA, so a vaccine against a particular tumor, reducing reduction in recurrence or death by up to almost 50%, 49%, which is amazing. So this is using markers which are 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's the takeaway with this particular late recurrence of cancer? Well, 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, stress, all drive that. There are some new detection tools. There are drugs that may help us stabilize that. And we're looking at personalized vaccines, which would 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 to 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. Well, 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 48 hours or thereabouts, many cancer cells will be under a lot of stress and strain from fasting. And that may be one way to actually help support, clear those cells. Look, I hope you found this presentation interesting. If you have or you know someone that it might be valuable for, please share it with them. I did put a lot of work into these, and I would love people to get the value that I try and put into it out of it. I always appreciate your time. So if you've got this far, I really do appreciate you listening this long. So thank you. I will be talking about CT radiation risk exposure sometime soon. Might be not sure exactly what order it'll be in. But if you are interested in CT radiation risk exposure, if you've 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.
