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Andrea Miyahira: Hi, I'm Andrea Miyahira at the Prostate Cancer Foundation. Today, I'm with Dr. Lloyd Trotman of Cold Spring Harbor Laboratory to discuss his team's recent Science paper, Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function. Dr. Trotman, thanks for joining us today.

Lloyd Trotman: Thank you for the invitation. It's really great to be here. We started this research some time ago, actually. And it was the idea behind our approach was to go very basic into the field of prostate cancer therapy. Since we're a modeling lab of prostate cancer. We model prostate cancer in mice, and we've been successful in making mice that die of metastatic disease, their own indigenous native metastatic disease. So we were wondering if we would be able to use that model to test therapies that aren't really very usual or standard of care at all.

And so one of the things that are important in prostate cancer is that there's kind of a prostate cancer specific situation that other cancer types don't share. And that is that most men diagnosed with cancer will not die from the disease because it's progressing very, very slowly. And so at the same time, most men that are diagnosed with prostate cancer will want to, therefore, adjust their lifestyle and diet in order to keep the cancer at bay and keep progression really down. So we have a huge population of men that want to do the right thing in order to delay the progression of the disease.

And so this has spawned a lot of clinical trials. And one of them was the starting point of what we're doing. Lots of men, and women actually, are interested in dietary supplements. It's a huge industry, and this is something that's really important, actually worldwide. So this is a store in the US. If you go to China, where I recently gave some talks, the exact same thing, everybody cares about supplementation, again, trying to do good to their body.

And so a huge trial was done in this respect on prostate cancer patients. And that studied the question whether antioxidants have an effect on prostate cancer risk. And so the result of that study that ended in 2011 is shown in this title: Dietary antioxidants actually increase the risk of prostate cancer. And so the study was called SELECT, for the Selenium and Vitamin E Cancer Prevention Trial.

It showed very clearly that the group of men that took something like 20 times daily recommended vitamin E intake in the form of a supplement had a 17% increased risk over that 10-year follow-up. And this was 35,000 men. So the significance was very clear. And it raised the question, if the antioxidants increase prostate cancer risk, would pro-oxidants do the opposite and delay prostate cancer or decrease the risk.

And so we studied that in our mouse model. And the answer actually was yes. So we have, in our typical trial, two groups—a water group. And we're plotting the disease progression in these animals. And the progression actually includes both metastatic and primary disease. And you would see in a water group, over a 20-week trial, it would be very significant progression of disease.

But when we put those animals on menadione, a classic pro-oxidant, in their drinking water, we would definitely stabilize the disease. We might have one outlier, but by and large, we would always keep the disease at bay. And this is important because in that same mouse model, we showed that if we do standard of care castration, we only get progression. So we might get some regression, but it's only short-lived, and the animals will actually die of a disease that has very bad kinetics and will kill them. And that's a situation that we're very familiar with—hormone therapy, anti-hormonal therapy in the clinic.

And so what's menadione? Menadione is a precursor of vitamin K. And we get it by and large from our diet. It's present in green leaves. It's also present in fermented products like cheese. And the plant version of vitamin K will be processed in the gut, releasing the menadione into our bloodstream. And then in cells, the cells will actually make our vitamin K out of that. And so we're looking at this molecule here that we're simply giving as a dietary supplement, so something that the body is very familiar with.

We found that this compound actually can cause a type of cell death that hasn't been described before. And I'm showing you a video here of what that looks like. So normal cells, when untreated—and we do a video on them—they will just proliferate on the dish. And this is like a six-hour video, six to 10-hour video of those cells just proliferating. When we give them menadione and we induce an oxidative stress, the cells will die. And you will see that there's the appearance of these bubbles inside the cells, and then the blebbing, and then they burst. So that is a new type of cell death that we labeled triaptosis. And it is caused by this oxidation, the oxidative stress that the cancer cells undergo.

And the important thing here was that we can completely antagonize that death and rescue the life of the cells simply by giving a reducing agent. Could be vitamin E, it could be—or it's not vitamin E, actually. It has to be a cytosolic reducing agent. We use cysteine here. So this is really critical because it told us that the cell, which has usually the power to muster reducing agents inside the cell, has per se its own means to fight the oxidative stress that we're introducing. It's just that the cancer cells usually do not have that. We have to supplement the cysteine so they live. If we just give them menadione, the cancer cells die.

And we were then able to look at this also in vivo. These are sections through mouse prostates where you see, again, the water-treated animals, they will have—red here—very strong and progressing prostate cancer, which doesn't just form glands, but actually shows cells leaving the glands. These animals will ultimately die of metastasis that comes from exactly these cells.

However, when we give menadione, we see a dramatic reduction of those red cells and no progression of the disease. And we also see that the normal prostate really doesn't care. So we have these nice epithelial luminal glands that aren't affected. So there appears to be a really good window. And so now, we want to obviously translate these findings from the preclinical models into several patient settings where we can study and compare the mouse situation with the human situation.

So this is the team that did the work. We've been doing this for about 10 years. The lead scientist here was Manojit. But the entire team was involved because there were so many aspects to this work. So thank you for your attention. I'm happy to take any questions.

Andrea Miyahira: So thank you so much. This is an interesting study. So was the menadione treatment able to cure any of your mice, or do you see any other treatments that you think may be synergistic with menadione?

Lloyd Trotman: So in terms of—we saw this stabilization of the disease. There were some animals that had barely detectable disease. The synergy is a very, very important question that we're following up most intensely, I would say now. So we're looking at other drugs. And we've stumbled upon some things that we think could be translated.

But we're also looking, for example, at the question of how hormones would affect the cell death of triaptosis. That's also an interesting question, whether antihormonal therapy is one of those synergizing aspects, or if they're completely separate and running in parallel. But I would say that on the basic research side, that's where we're most likely to find something very important in the near future.

Andrea Miyahira: OK, thank you. And what is the role of the triaptosis pathway in normal cells and what side effects would you anticipate with using menadione treatment?

Lloyd Trotman: Yeah, so in terms of the side effects, it seems to be, as we were able to show in one of those last slides, that normal cells are extremely resilient to this oxidative stress. And this brings us back to the mere fact that the ability to maintain a reducing cytoplasm seems to be a core ability of living cells. In fact, the live-death cell assay that everybody uses when they do drug kill assays is measuring the cell's ability to maintain a reducing environment.

And so normal cells seem to be very good at that. And it's the cancer cells that seem to not really live up to that stress test as much. So that's why we hope there's quite a window there. And so triaptosis might simply be the realization of a cell that it can no longer maintain that balance. And therefore could be under viral attack, could be under any attack. The outside-inside barrier is compromised and it wants to shut down.

Andrea Miyahira: OK, thanks. And what dietary means could people use to achieve the effects of menadione? And do you think this approach is preventative or whether it actually prevents progression in established tumors?

Lloyd Trotman: So the simple answer would be eat your greens because that's where the green is, where the natural menadione actually is. There are some actually fermented foods, especially in Asia, that have very high levels of menadione. And obviously, we're very interested, knowing that Asia, Japan, China have very low prostate cancer rates, to see whether that's actually a natural protection that they are getting. But the key to all of this is we need to be able to measure menadione. We need to be able to measure it in men, in the circulation, and in the prostate. And so I think that's where we are able to then translate our findings. And whether, in the end, the diet would be good enough or it would be a pill is up in the air. But as long as we can measure it and correlate effects and the dose.

Andrea Miyahira: OK, thanks. And what are your next research steps and are there any translational plans?

Lloyd Trotman: Yeah, so as mentioned, we're using the mouse to really learn. And our biggest goal is to get this into patients. And that's where we need help. We're thinking about whether we should be using the compound as is, the menadione, or whether we should use the derivative. And that is a question of optimization. We may not—menadione can also lead to clotting, not something that we would want in elderly men. So ultimately, there may be a path to remove that feature.

But we need to, again, be able to measure in a patient. And we're thinking that this could be doable either in the active surveillance patient group where there's repeat biopsies, and we could measure it in the biopsy of men that are taking it, or in the neoadjuvant setting before a radical prostatectomy where the sample is there. And so we would want to learn the step by step. And we're just happy and glad to have a really faithful mouse model where we can test all of these things before going into the patient.

Andrea Miyahira: OK, well, thank you so much, Dr. Trotman, for sharing this really interesting study.

Lloyd Trotman: You're welcome. You're welcome.