But she's really flourished in her own right and has sort of taken over the cancer side of that lab looking at nutritional interventions for cancer. And it's a really exciting field because when you think about how prevalent cancer is, pretty much everybody has been touched by cancer, either personally or by a loved one.
And cancer therapies, although you can say we've progressed, probably haven't progressed as quickly as many people would've hoped with this sort of genetic basis of cancer. Well, now there's this resurgence of this whole other concept of the metabolic basis of cancer. And how can we treat metabolic disease? With diet, with nutrition. And specifically with a ketogenic diet and maybe even exogenous ketones.
Now there's a lot of excitement about this field, but as you'll hear Dr. Poff and I discuss it, still a lot of preclinical evidence, which puts us in a bit of a tough balancing act of how strongly to promote this because people want a cure, people want something to help, they latch onto anything. And if we have something that can help them, we should be promoting it.
But does the strength of the evidence support the strength of the recommendation? So we do have to be a little bit careful when we talk about nutritional therapies for cancer. They play a role for cancer therapy and for helping the patient, but exactly how strong can a recommendation be? And I think that will be an important take home from this discussion with Dr. Angela Poff.
She's got a ton of knowledge, she's done a lot of experiments in this field, so I hope you enjoy this and really come away with a few nuggets of what it means for nutritional therapy for cancer therapy, what the state of the evidence is now and maybe how can you take some of this either personally or to help a loved one who is maybe suffering with cancer. So enjoy this interview with Dr. Angela Poff.
Dr. Angela Poff, thank you so much for joining me on the DietDoctor podcast.
Dr. Angela Poff: Absolutely, very happy to be here.
I went straight into a PhD program after my undergraduate and kind of how these programs work, you typically show up at the University and you enter into like an umbrella program where they have a lot of different departments under the program and then you meet with all the professors and you learn about what kind of research they're doing and then you choose one to do your doctoral thesis with.
So at that time Dominic had just transitioned into a faculty position at the University of South Florida and so he was wanting to start up his own lab. And at that time he was doing mostly neuroscience research, so he had been funded by the Navy to look at mitigation strategies for central nervous system, oxygen toxicity seizures. And as we know, ketosis is a potential therapy for seizures and that was an application that he was studying- My headset is going to fall off... Sorry about that.
And I just remember like in that moment my whole kind of mindset shifting, because I'd never thought- I knew that diet and nutrition was important for like prevention of disease and maintaining health but I'd never kind of viewed it as a tool to actually potentially treat disease, especially for something so severe and complicated as cancer.
And a decade later, you know, we still work together in that set up, and it's been great, we have a lot of students and people in the lab working on various projects. It's really expanded since those days. So it was completely by chance, I was totally lucky to end up at that program and to meet Dom.
One, non-toxic... why? Because so many of our cancer treatments are toxic. Wouldn't that be wonderful if we could find something that's non-toxic? And then the second part, metabolic targeted therapy. So, that's the part I want to unpack a little bit, because when I was going through medical school and residency, it was sort of this genetic boom of the genetic cause of cancer. And it almost seems like it's a "new revelation" that cancer also has this metabolic aspect, but in truth there's nothing new about it, is there?
And so Dr. Otto Warburg who is a German biochemist in the early 20th century had done research looking at the metabolism of cancer cells and found that they were very different than a normal cell of the same tissue type, and that they preferentially will utilize large amounts of glucose metabolism and they don't rely as much on oxygen - oxidative phosphorylation and oxidative metabolism to fuel their growth.
They definitely do retain some level of oxidative metabolism and some cancer types more so than others. But it's almost a universal feature of cancers that there's heightened a glycolytic metabolism and the more aggressive the tumor is the more metastatic it becomes, that feature exacerbates even further. So much so that this is actually a diagnostic tool.
It's the basis of a diagnostic tool, the FDG PET scan that is basically just radioactively labeled sugar and the patient consumes this and then the tumors take up the glucose, the sugar, at such high rates that it will visualize them on this PET scan.
So the same genes that we know of as being heavily mutated in cancer that are stimulating, you know, cell proliferation, inhibiting apoptosis, all of these things that we think of as being those fundamental genetic kind of features of cancer, they also control metabolism. So you can't even really separate them. And a lot of these genes, when they're mutated in the ways that are typically seen in cancers end up with this more glycolytic metabolic phenotype.
So the glycolytic anaerobic phenotype of cancer is actually something that we see in proliferating cells in general. So stem cells for example, have a more glycolytic phenotype typically because they are proliferating. So it's also just a natural feature of a rapidly proliferating cell to do this and there's some important reasons for that.
And kind of the biggest idea is that glycolytic metabolism, if you're not fully oxidizing the substrates through the respiratory chain and completely losing carbons to CO2 production, you can actually shunt those carbons towards biomass synthesis. So this is actually the idea- there is kind of this- two competing theories on why tumors are glycolytic and I think it's true that both sides of the coin are kind of true.
So essentially, this glycolytic phenotype allows these carbons to be preserved and instead of being fully oxidized you get to package, repackage them into new lipids, new proteins, new DNA, which if you're a growing tumor, you have to be able to grow.
So, if you use one of these gene targeted therapies, you may be getting the majority of the tumor cells but not all of them, but if you focus on the metabolic side as well, chances are you're getting practically all of them... would you say all of them?
So another area of cancer metabolism that we target in the lab, in the hyperbaric lab that I work in at the University of South Florida is targeting the hypoxia that's present in tumors. So as tumors grow, they have to form new vasculature to provide blood to that new area of the tumor, but they're doing this, the angiogenesis that's stimulating these new blood vessels to growth, is happening under the direction of these mutated gene pathways.
So it's not a normal process in these- These vessels that form are insufficient, they are immature, they have leaks, they have holes in the walls and so and they can't keep up sometimes with the growing tumor. So throughout the entire tumor you have everything from complete anoxia sometimes-
So it's quite complicated and all of these things are kind of converging at once, but it results in this real mixed bag of the tumor metabolically, genetically. There are regions, sub-regions throughout the tumor that have different mutations, different metabolic features that mean any single targeted therapy is less likely to actually impact the entire tumor. And indeed that's what we see. This is why most targeted drugs end up with resistance.
You may apply a drug that is targeting a mutation that is even if it's present in 80% of the cancer cells, you still leave 20% behind. And now there is ample room for those 20% to repopulate. And that is repopulating from the portion of cells that were resistant to your treatment in the first place and now the tumor that recurs is resistant to that treatment.
So unlike a targeted cancer drug that may be influencing a specific genetic mutation, the ketogenic diet is changing hundreds of metabolic pathways at once. It's also influencing a large number of signaling pathways simultaneously through epigenetic alterations.
So I think that the ketogenic diet because it's influencing so many things at once, that's why we see that at least the preclinical literature suggests it may be effective to some degree in a larger number of cancers.
Cachexia is the wasting that occurs in late stage cancer. So where you'll lose body fat, but most importantly muscle mass. It contributes to the morbidity and mortality of patients significantly and is even thought to be responsible for mortality in about 20% to 30% of cancer patients. So when you're talking about a diet, especially a diet that is publicly used to lose weight in a cancer patient, there's a lot of fear there which is totally fine and understandable about how do we walk this line.
But from a clinician's perspective this is so important and historically we've only kind of- the advice has always been eat whenever you can to keep your body weight up. For a good reason, I understand that because they know that if a patient with terminal cancer starts losing lots of body weight, that's a very bad prognostic factor.
And that's really the beginning of the story. So, glucose levels of course do go down on a ketogenic diet. Not necessarily vary significantly depending on where your baseline was of course. And that will reduce glucose availability to the tumor. There's human data showing that in patients on a ketogenic diet from these studies, about 20% less glucose being taken up by the tumor.
That's going to be tapping the brakes, some, on those important proliferative pathways that really thrive on that high glucose flux within the tumor, but that's not a starving the tumor of glucose, right? For me I think perhaps at least as important is the insulin story. So as glucose goes down, insulin goes down. Insulin is a very important growth factor for cancer. Many, perhaps most cancers overexpress insulin receptor, have overactive insulin signaling which contributes to the growth and proliferation.
And so they actually silence- we have a host of genes that are inherent important genes to tell ourselves to stop dividing when you shouldn't be dividing. As an adult, not many cells in our body are actively dividing at one time. But those genes are still in our DNA from when we were growing in development to do that. So cancer finds a way to turn those genes on and to turn off the genes that are the housekeepers saying, hey wait, let's pump the brakes, or there's something wrong with that cell, we need to initiate cell death, so that it doesn't become cancerous for example.
And they do this in one mechanism, they do this through mutations, but another way is that they actually epigenetically silence those genes. So literally the DNA, the chromatin around those genes gets twisted up tighter and tighter so that they can't be transcribed and then translated. So ketones function to reopen up DNA in some important targets that we know cancer might be benefiting from.
So we actually see that tumors may be- you know, cancer may be inhibited by ketones, because the ketones are actually re-expressing these tumor suppressor genes simply by a signaling mechanism. This has nothing to do with their energy status. So ketones have two complete faces. They can be burned as energy and make energy ATP or, you know, they also can just physically interact with other proteins, they bind to cell surface receptors; we're now learning more and more about the receptors that ketones bind to and what, you know, effects happen in the cell, downstream of that.
And then they also interact with the DNA, they also interact directly with components of our immune system. So there's even data that suggests that that component of ketones signaling is contributing to the anticancer effect in at least some of these preclinical models where ketones influence the immune cells ability to recognize and then target the cancer cell. It's amazing.
So when it comes to general health concepts of a ketogenic diet, you know, I generally say you don't need to chase ketones. Because there is a ketone level- a beta hydroxybutyrate level of 3. Any better than a level of 1, when it comes to insulin sensitivity and weight loss...
And maybe they have some of these weird epigenetic, you know, suppression going on, but it's not really that important for the success of that tumor, at least at that time. In that state a ketogenic diet that lowers glucose may be important and the ketone story might not be as important, because they're not as dependent on the mechanisms that this ketones signaling would target.
But what about a tumor that is really, really benefiting from the epigenetic silencing of these tumor suppressor genes? And maybe they are actually more oxidative in its capacity than a normal cancer. Well, in that case maybe the glucose side of the ketogenic diet is not as important for the tumor, but the signaling part is really important.
So when we talk about the ketogenic diet, are we talking about the specific type of ketogenic diet for cancer therapy, like the 4 to 1, where there's four times as much fat as there is protein and carbohydrates combined, which is not probably the average ketogenic diet that most people are eating. So do we have to make that differentiation when we talk about a ketogenic diet for cancer therapy?
In my opinion at this point and I think this is what's been done mostly trying that strict therapeutic level, giving yourself the best shot, giving yourself the best shot to reduce glucose, reduce insulin, while also getting ketones higher, that makes sense as a let's get into clinical trials in this way and then we can tease out... in what situations might just simple low-carb versus a ketogenic also be effective? That might be the case.
This is what we have seen in epilepsy. For the first several decades it was all this 4 to 1 ketogenic diet and within the past couple of decades people have started saying, okay, a low glycemic index treatment is actually sufficient for this type of seizure disorder or a modified Atkins or a modified ketogenic diet is sufficient, but we're just not there yet.
So the type of fat in these mouse studies makes a difference too, because that's not what people are eating. So the different types of fat may have different types of effect. So that's one of the problems when trying to extrapolate mouse data to human data as well. So we clearly need more human data. So when is that coming? Hurry up... when is it coming?
But it was not something that was being discussed on a main stage and it was not something that most oncologists had heard of or were open to in any way. We at that time, you know, in those early years would reach out to local cancer hospitals and just try to get perspective or, you know, even just like, "Can we come and give a presentation about this, talk about this?"
And there's a lot of pushback. Fast forward, a few years later, and we're getting contacted by those oncologists, because they want to know, right? Things have changed so quickly.
So I would say even for, you know, science where things move slowly, this is accelerating very rapidly, in part because conversations like you and I are having right now, getting information in people's hands that they can go back to their oncologists and ask questions and oncologists now, you know, realize, "I need to learn more about nutrition."
It's not something that I covered in my training. And so, you know, that's why these kinds of conversations are so important, just getting the information out there so we can all move forward together.
So I think this is important because from what I understand renal cell carcinoma and melanoma are two cancers that really don't respond to a ketogenic diet or may even worsen with ketones at least in mice compared to other tumors. Now is that true and why would there be a difference?
So that same mechanism, the acetoacetate simulation of that pathway is something that's also been reported to happen in skeletal muscle, which is why skeletal muscle can be preserved in models of skeletal degeneration. So this is a signaling effect, a unique signaling property of acetoacetate specifically that promotes this pathway. This pathway happens to be really important for a melanoma that carries that specific mutation.
So how important is glucose metabolism in that tumor? Is it as important as that signaling pathway or more important? Even then you might have a net negative effect on the tumor depending on the importance of the things that are being targeted.
And so there still is a bit of a limbo, but is there any- can you draw any lines to say for these cancers, you know, even though it's not guidelines, even though I can't tell people individually, I would say, in general try it for these cancers and for these cancers maybe not? Of course in addition to radiation, chemotherapy, surgery, whatever the general recommendations are from the cancer doctors.
So, obviously I'm not a medical doctor, I am a scientist, I can only speak to what the data suggests is happening and what might be most useful versus not. I don't give any medical advice of course. I would say that there are types of cancers that there have been a lot more data in, which is why they are the furthest along in clinical trials, they have the most clinical trials; a great example would be brain cancer.
So the most preclinical data for a ketogenic diet for cancer comes from brain cancer. Brain cancer, especially GBM, glioblastoma multiform stage 4, brain cancer. Also, even with standard of care it has a very grim prognosis. So in that setting it really is the perfect scenario to test this out. And that's why there have been the most number of trials, right?
So there's a lot of preclinical studies and there is some clinical data that shows that this might have a nice effect there. All the other cancer types, it's mostly coming from preclinical data, saying that we need to test this. I would say the ones you've mentioned, you know, the melanoma story, that's obviously complicated, especially for those BRAF V600e mutated patients and we need to be more cautious.
And then the renal cell carcinoma that was interesting because that was basically a portion of renal carcinoma patient will present with a paraneoplastic syndrome called Stauffer's syndrome that basically causes inflammation in the liver and liver failure. And so the study that showed this might not be a good idea for renal cell carcinoma was not because it was promoting the tumors. The tumors were actually growing more slowly in those mice. The mice died because they developed this paraneoplastic syndrome and caused liver failure.
Because, let's face it, chemotherapy is toxic and people can get severe side effects. So, does the ketogenic diet, and then we can also talk about plus minus fasting, help with those side effects of the chemotherapy?
This is all theoretical, of course, at this point. Those things would have to be pinned down in a clinical trial. But for a few reasons, we think that, yeah, it might actually improve other aspects aside from just effect on tumor. We need to be thinking about quality-of-life.
In that basically they showed they had developed these drugs against PI 3 Kinase inhibitors- they were PI 3 kinase inhibitors to target that pathway, but they weren't actually doing very well, they didn't have great success. And what they found out was basically... the tumor was reactivating essentially insulin signaling around it just as like to bypass the inhibitor.
And so what they found was it can do that. The tumor can reactivate the insulin to like circumvent that drug in the context of a standard high carbohydrate diet, but if you put a ketogenic diet on top of it, it's not able to mount the insulin response that compensates and overcomes that drugs effect. And so the background diet made all the difference in whether or not this drug actually worked. So that was such a great paper.
Of course, it was done by incredible researchers that are just at the top of the field and published in a very high impact scientific journal. But that showed unequivocally diet matters not just from its own impact on cancer, but it actually impacts our ability- the chemotherapy drugs that are being used and their ability to do their job as well, which is pretty cool.
Or do you think it's going to be much more effective in stage 4 in the metastatic disease and less so in the early on? Because like you were saying, when it's metastatic it's growing faster, it's more glycolytic, that's where you can sort of impact it more. Or can it still be effective sort of in the early stages of cancer?
Usually by this time the tumor is really resistant to a lot of therapies. So even though maybe the intervention of ketosis at that point could impact on its own stronger, you don't have as many options. So with cancer and just how aggressive and smart it is, I'm a big, big proponent of as early as you can get it, and as early as you can start fighting it, the better. But there are reasons why it could potentially be applied across the board, but that's something we have to tease out for sure.
So even people who aren't personally touched by cancer yet, in the back of their brain they're probably thinking "Can this be a prevention strategy?" And of course we don't have the data, but is there enough theory, theoretical reasons to say, yes it could be?
So just first of all, not eating, you know at least a high glycemic load diet should, you know, theoretically the data suggest that it would lower that risk at least or maybe neutralize that increased risk. It also, you know, just things that- it targets things that we know increase your risk of cancer: obesity - strong link between diabetes and cancer.
So you're lowering your glucose, you know for the most part you're seeing lower A1c, you know, all of these things are independent risks for developing cancer. So it makes sense, we don't really have data because it's hard to do that kind of trial. What we're talking about is, you know, decade-long data following people eating in a certain way... and do they have lower cancer risk?
So, theoretically you're getting the enhanced mTOR signaling, but, you know, it's not- I don't know, it's so hard to say. I would say overall when we look at all of these independent changes that are occurring, the bulk of them seem to be moving in a good direction that suggests a lower cancer risk.
There is one study... Adrienne Scheck performed a study in a brain cancer model and the ketogenic diet on its own prolonged survival, radiation on its own prolonged survival... In that model when she combined radiation and ketogenic diet she saw a complete remission, sustained complete remission for like a year, which is a long time for a mouse; they only live about two years. In those animals, in like 80% of those animals that got the combination therapy, that's the closest I've ever seen to a cure. But again it wasn't just the ketogenic diet and it was in a brain cancer mouse model. Right?
But it's not just a one weekend event a year, we put out information throughout the whole year. So we are on all the social platforms. And our website is metabolichealthsummit.com And so we we're constantly putting out more information. So I can be contacted there or you can find out more about what we're doing through those resources.
