Siddhartha Mukherjee and Anand Parikh On A New Way To Fight Cancer

Kara Miller:

Welcome to Instigators of Change, a Khosla Ventures podcast, where we take a look at innovative ideas, the people who come up with them, and those who invest in them. I'm Kara Miller. And today, tough talk on cancer, which has been a top killer in America, for decades.

Siddhartha Mukherjee:

In the 2000s, the idea was that, "Oh. We would sequence cancer cells, find genetic mutations in them. And then, find drugs, that target those genetic mutations."

Kara Miller:

The physician and writer, Siddhartha Mukherjee, says, "That idea, mostly fell flat. And it's time to admit, we badly need something new."

Siddhartha Mukherjee:

We have, as a community, we have to acknowledge that. If we don't acknowledge that, we will be not a scientific community, but something else.

Kara Miller:

Mukherjee and Anand Parikh, co-founders of Faeth Therapeutics, talk about a different way forward.

Anand Parikh:

We're not going to chemically engineer our way out of this problem. I think we've got to think orthogonally and really do the physiological work, to starve these tumors.

Kara Miller:

That's just ahead, on Instigators of Change. After Neil Armstrong landed on the moon, in 1969-

Neil Armstrong recording:

"That's one small step for man one. One giant leap for mankind."

Kara Miller:

... Richard Nixon, triumphantly, announced, and this was just a couple of years later, what became known as America's Cancer Moonshot. The goal being, as Nixon said, "The conquest of cancer."

Siddhartha Mukherjee:

It's a little bit like saying, "We're going to send a rocket to the moon, without knowing Newton's laws."

Kara Miller:

Siddhartha Mukherjee is a physician, focusing on cancer, and an assistant professor of medicine, at Columbia. He won a Pulitzer Prize, for his book on cancer, The Emperor of All Maladies.

Siddhartha Mukherjee:

When The Cancer Moonshot was launched, we understood very little about cancer. This was a time, when there was a big debate about, "What cancer is, as a disease? Is it a viral disease? Is it a genetic disease? Is it a combination?"

Kara Miller:

"Treatments were also perplexing, to doctors and researchers. And there was a real danger to this Moonshot," Mukherjee says. "People thought, kind of like the actual Moonshot, in the 1960s, it was going to result in something concrete. We had landed on the moon. Maybe, now we would conquer cancer, but then we didn't. So here are the statistics, more than half a million Americans die of cancer, every single year." Mukherjee has become convinced that we just have to do something different. "And that," he says, "Means looking back, at some very old research, which may never have been really embraced, in the way it should have been."

Siddhartha Mukherjee:

Almost a hundred years ago, starting with work done by Otto Warburg, there's been this idea that, in terms of metabolism, cancers share, very, very different cancers, breast cancer, leukemias, pancreatic cancer, share a metabolic dependence on nutrients.

Kara Miller:

So what if you could figure out, how cancer cells, which behave differently and deal with energy differently, from other cells in your body, what if you could figure out, just what nutrients the cancer cells need to thrive, and then not let them have those nutrients? Mukherjee is seeking to answer that question, as a co-founder of the company, Faeth Therapeutics, along with several fellow researchers and physicians. Anand Parikh is also co-founder of Faeth Therapeutics, where he serves as the CEO.

Anand Parikh:

The research base is becoming overwhelming, that this is almost certainly a new therapeutic approach, akin to surgery, radiotherapy, or drugs, that precision nutrition is just waiting for its time in the sun, as it relates to cancer treatment.

Kara Miller:

And just to go further on that, for lay people, what the heck is precision nutrition? And what have people found, in the lab? What kinds of manipulations of nutrition have they done and what have they done to the cancers?

Anand Parikh:

Yeah. I think, these are very specific manipulations, intended to look at, "What's the organ of origin?" So, as Sid said, "Is it breast cancer? What's the prevailing genotype? Is it HER2 positive? What's the drug that's being used to treat this cancer?" And then, we look at the nutrients that are needed, by that particular tumor type. And that's where we find the commonalities, that Sid was mentioning. And we've seen research on things as varied serine and glycine deprivation, insulin deprivation, histidine supplementation, methionine, these very specific nutrients.

Anand Parikh:

We find that particular tumors or particular groups of tumors, as Sid alluded to, have an excess reliance on these things. And that, if you take them away, it harms them. And what we've seen, in many of the preclinical studies is, tremendous, tremendous outcomes. In some cases, greater than we would see with traditional drugs. Literally, diet being more powerful than chemotherapy, in preclinical models, in pancreatic cancer. A horrible, horrible disease, that now, we're hoping to bring some potentially new treatments to.

Kara Miller:

Sid, let me switch over to you. When we think about these really obscure nutrients, that many people have never heard of, what does it mean, to an actual patient, to try to deprive this cancer mass in their body, from getting access to one of these nutrients, that, apparently, the cancer does really well with?

Siddhartha Mukherjee:

Well, first of all, let me just say, that these are not obscure nutrients.

Kara Miller:

Okay. Okay.

Siddhartha Mukherjee:

These are-

Kara Miller:

We may not have heard of them, but it doesn't mean they're obscure?

Siddhartha Mukherjee:

... Yeah. These are fundamental nutrients, that cancers and our bodies depend on, in order to function physiologically. So these are nutrients, that we can manipulate because our body can make them, but cancer cells are uniquely dependent on them. I often like to use the analogy of the Achilles Heel. Cancers have Achilles Heels, too. We just have to find the Achilles Heel. And these are nutrients that our bodies can make, our bodies can survive with, our bodies can even survive without, because we can make them ourselves, but cancer cells are uniquely dependent on them. If you deprive them of the nutrients, the cancer cells shrivel up and die.

Siddhartha Mukherjee:

So I really think about nutrition, as a completely novel axis of oncology, of cancer therapy. It's never really been fully explored. And it's a novel axis. It's an axis that really lies outside the traditional chemotherapy radiotherapy, surgery axis. Because no one has, aside from experiments done a hundred years ago, no one's really fully looked at how important it is for a cancer cell to have nutrients. Because nutrients are the ways that cancer cells grow, there's no other way. There's no other mechanism, by which they can grow.

Kara Miller:

So just on a practical level, what does it mean for Joe the cancer patient, not to have, I don't know, glycine in his diet? What does it practically mean, for this person who has cancer? What do they do on a day-to-day basis?

Siddhartha Mukherjee:

It means, changing the diet. But let me emphasize, that these are not radical diets. These are diets that we've devised and are continuing to devise, that have to do with very particular manipulations. And these very particular manipulations have to do with maintaining normal diets, normal nutrition, normal energetics, but with something that's different.

Kara Miller:

Okay.

Siddhartha Mukherjee:

And those differences, I think, the emphasis is on the fact that these are tolerable, achievable. These are not like, you go on some crazy blueberry-

Kara Miller:

Fasting diet?

Siddhartha Mukherjee:

... fasting, etc. etc.

Kara Miller:

Okay. Okay.

Siddhartha Mukherjee:

These are very specific, precision diets, which almost mimic your normal lifestyle, except you, and you wouldn't notice it, but the cancer cell would notice it.

Kara Miller:

Okay.

Siddhartha Mukherjee:

Anand, do you have any thoughts about it?

Anand Parikh:

Yeah. I think, that's very fair. And, I think, Sid mentioned the variegated nature of all these tumors. And the diets are just as multitudinous, right? It will be different, for each particular group, that is taking a particular dietary intervention, it will be different. The precision nutrition will be different. So whereas, someone who is being deprived of glycine may have particular type of diet, someone who's being deprived of cholesterol, theirs will look very, very different, so there are differences there. I think, one thing we've tried to do, as a company, is, as Sid mentioned, make it as easy as possible on the patient. So we will send them, literally, everything they need, to their door, to make it as absolutely easy for them to comply, as possible.

Kara Miller:

Underlying all of this, it seems clear from what you're saying, is this idea of precision, that everybody's different. So it feels like, underneath all the food and thinking about amino acids, is a pretty hefty level of, I think, this wave that we're kind of part of this idea of precision medicine, of using computers, to figure a lot of things out, about, "Who needs what?" Is that fair?

Anand Parikh:

I think, that's absolutely fair. And I'd like to draw a line. Sid talked about Warburg and his initial work, in the 1930s. And then, how Sid, and Lou, and Karen, and others, have been publishing papers, over the last 10 years, showing how thinking about organ of origin, genotype and drug can provide us with a level of specificity, that, maybe, Warburg didn't foresee. And, I think, in the future, once the FDA is able to contemplate this, I think, we're not just going to see small slivers of people, on very specific diets. I think, we're going to see [inaudible 00:11:33] precision nutrition.

So at the breast cancer patient, the two patients, who Sid mentioned, who have breast cancer, but are very different in terms of their mutational status, in terms of the physiology and the etiology of their tumor, will have slightly different precision nutrition prescriptions. And the way we figure all of this out, because, I think, the data is so voluminous, that it's too difficult, for any one person to comprehend, is, we have a machine learning system, that literally spits out the difference in every single phenotype, genotype, of tumor and the difference between use and production in nutrients. And from that, we can then surmise, that a particular tumor will have different needs than another one, that otherwise, might look quite similar.

Kara Miller:

So this could be for either of you. And it's a bigger question than Faeth, because if so much importance is placed on the machine learning, the data analysis, that has to be done, because, as you said, there's so many inputs, no person's going to sit down and compute this, are we there, yet, with how good data analysis is, how good machine learning is? Because, I think, people think of curing cancer or getting further with cancer, as reliant on men and women pipetting things, in a lab, right? But we're really talking about a different set of tools. And I just wonder, how far along you think those tools are?

Anand Parikh:

We're talking about the both of those tools, together. So we're talking about using machine learning, to help stratify the world of cancer. And then, using experiments in the lab, to further drill down and validate, so, I think, it's a mix of both. The other thing, I would say, is, that even if the machine learning isn't good enough, today, or isn't where we would want it to be perfect, today, unfortunately, neither are cancer drugs. So we see this situation, where I was thinking about a drug called Enhertu, that got a standing ovation, at ASCO, with a 40 odd percent response rate. We won't be perfect, in having every patient respond to a particular precision nutrition intervention. But even if we break those 30%, 40% thresholds, it can be practice changing, for many diseases.

Kara Miller:

Sid, what's your take on this?

Siddhartha Mukherjee:

Well, I would echo Anand's ideas. And, I would say, that's not 40% or 50%, because it will likely be more. Because, what we are targeting are not particular mechanisms or genetic mutations that drive cancers. We are targeting the general physiology by which a cancer cell grows. And that's been The Holy Grail, to some extent, of cancers. In the 2000s, the idea was that, "Oh. You know? We would sequence cancer cells, find genetic mutations in them. And then, find drugs, that target those genetic mutations."

Kara Miller:

Right. Right.

Siddhartha Mukherjee:

That was the big idea. That idea, I think, has turned out to be, aside from a few cancers, a grave disappointment. And we have, as a community, we have to acknowledge that. If we don't acknowledge that, we will be not a scientific community, but something else. I'll give you an example. After about two decades of research, a drug was created, around one of the biggest drivers of cancer, called KRAS. It was a drug that was specific to that mutation. And it was specific to the idea that that mutation would drive the cancer's physiology. When the drug was used in a clinical trial, it was a positive clinical trial, all good, but the progression-free survival was nothing that one would applaud. 12 months, 18 months, I don't remember the number.

This is a reminder that cancer cells are incredibly plastic in terms of their capacity to resist drugs that are targeted to the mutations that drive their growth. And, I would say, that we, as a community of oncologists, have turned our heads away from the idea, in the 2000s and 1990s, that there was a linear idea, "Find the mutations, target the mutations, kill the cancer cells, end of story."

Kara Miller:

Right.

Siddhartha Mukherjee:

It has not worked out to be that, so we need a new paradigm. And the new paradigm is to say that, "That old idea was a good idea, but it wasn't right." And so, we need a new paradigm. And new paradigm has to be, that we need to target fundamental physiological mechanisms in a cancer cell, that are different from a normal cell, and thereby, target cancer. It's a completely new idea. And I cannot emphasize how revolutionary and how much of a difference this is, in the standard thinking about cancer. The standard thinking about cancer is, "Oh. You have cancer, sequence it, find the mutations, and find the drugs that will target the mutations."

Kara Miller:

Right.

Siddhartha Mukherjee:

That has not worked. It has not worked, not only with minor mutations, it has not worked with mutations that are known to be the major drivers of the cancer cell. So we can put, like ostriches, our heads in the sand and say, "Oh. Let's go on this way." That has not worked. And if we keep putting our heads, like ostriches, in the sand, it will keep not working. We need to find a new way forward, which lies outside this kind of linear logic of, "Find the cancer, find the mutation, and find a drug that blocks the mutation," that is not working.

Anand Parikh:

One thing, I would add, I think, what Sid said is so important because it totally undercuts the prevailing orthodoxy. And, I think, it takes a lot of courage. And I'm not sure there are a lot of people with enough courage to say what Sid just said, that, essentially, evermore a fine grain discovery of smaller and smaller mutations and better chemistry, is not going to solve this problem of cancer. We're not going to chemically engineer our way out of this problem. I think, we've got to think orthogonally and really do the physiological work to starve these tumors.

Siddhartha Mukherjee:

And let me add more to that. I've tried to understand the prevailing orthodoxies and I've tried to reconcile myself with them. And no one was more excited than me, when we found a drug that would target one of the great mutations drivers in cancer, like KRAS. And yet, no one was more disappointed in the results. And so, we have got to change. We have got to think of new paradigms.

Kara Miller:

Do you feel like it's an issue of ignoring something that's systemic? I mean, it sounds, from what you're describing, like, you've got a building and people are looking for the brick, that's messed up. But in fact, the problem is the air conditioning system. It's something that is not confined to just one little place? It's more, part of how the whole entire system works?

Siddhartha Mukherjee:

I've been saying this, forever. I mean, I think, that cancer is a physiological disease. The cancer cells are physiologically different, from normal cells. And the more we explore that physiology, outside finding mutations, is the best way to move forward. I wrote a piece, in The New York Times, called, Cancer Should Not Be About Mutation Hunting. Cancer is a physiological disease. Most diseases, every disease that we know of, is a physiological disease. By physiology, I mean, it integrates multiple aspects of human biology. There are signals that go between cells. These signals can counteract or even inactivate drugs that we send with great precision, to cancer cells, and cancer is one of them. So I stand by my belief that, unless we understand cancer at a physiological level, we aren't going to move forward.

Kara Miller:

Anand, let me ask you a little bit about food. One of the things I've found, over the years, is, I've spoken to different doctors, different researchers, is that, food, even though we know it is very important in keeping you healthy, it often doesn't get that kind of credit. I mean, there have been little programs, where doctors are allowed to prescribe vegetables and you might be able to get those for free. But if you find that food really can help with cancer, how do you get an establishment that's really about pills and other kinds of medications, to accept food as part of health and medication?

Anand Parikh:

I think, that's a great question. I think, the first thing is proving efficacy. If you can prove that this treatment modality can deliver outcomes that are of the level or greater than traditional therapeutics, I think, there will be a ground swell, from the patients, themselves, saying, "Look. This is something we need to have access to because it's going to help us live for longer and potentially cure disease."

And so, I think, in many other disease states, the power of food is already recognized. You look at diabetes. You look, even, at cardiovascular disease, to a degree. You think about inborn eras of metabolism, irritable bowel syndrome, pediatric epilepsy. There's a variety of diseases, where we do acknowledge and understand the power of food and either managing or treating those diseases. I think it's only a question of time, until it comes to cancer. And once it does, and if it demonstrates efficacy of the same degree or greater than drugs, then there's no reason why it should not be paid for, at parity, in the same way. I've often said this and I often repeat it, but I really do mean it. I hope that if Faeth is successful, that we have 100 competitors very, very quickly, because we alone will not be able to do the work needed to truly explore this entire new axis of treatment. We need a lot more people in the space very, very quickly.

Siddhartha Mukherjee:

And Just to add to Anand's point, food is a chemical. Chemotherapy is a chemical. Targeted therapy is a chemical. There is no fundamental difference between food as a chemical, chemotherapy, as a chemical, targeted therapy, as a chemical. These are all the same things, they just come by different names. If a chemical or an enzyme, like L asparaginase, can deplete asparagine in the body, and thereby, really make a difference in pediatric leukemia, there's no fundamental reason why depleting asparagine, in another way, whatever it might be, could make a difference in pediatric leukemia. They're just chemicals.

And the idea that food is not a chemical is absurdity, because, of course, it is. So my general point is that, as a chemical, food has been underexplored and should be more deeply explored, as one other axis of chemical therapy for cancer, in which we are not dependent, so much, on, as I said, the, "Find the mutation and find the drug," strategy, which has not worked.

Anand Parikh:

And, I think, one other thing to add to that, the precision nutrition interventions, we are talking about, Kara, and not things that, generally, an individual can do by themselves.

Kara Miller:

Okay.

Anand Parikh:

Earlier on, you said, "Well, what it would an example be?" If you're depleting serine, glycine, and proline, nobody's going to have any idea where to start and how we do it.

Kara Miller:

Right. Right. Does that mean I order pizza or pasta? Nobody knows. Right.

Anand Parikh:

And it's not that simple, right?

Kara Miller:

Right.

Anand Parikh:

So it is a chemical, in many ways, that looks and feels, to the patient, like food, but there are drug-like components to it, as well.

Kara Miller:

Do you see precision nutrition as doing the heavy lifting, here? Or is this a situation, in which, I mean, I know there have been studies where, let's say, a diet, a keto kind of diet, has made a drug much more effective, because that kind of diet appears pave the way, for a drug to actually work? You know what I mean? Can you give me a sense of, is this an in conjunction thing? Or is this an end, in itself?

Anand Parikh:

I think, it can be both.

Kara Miller:

Okay.

Anand Parikh:

I think, in some cases, you will see precision nutrition that makes adverse events disappear and that makes the drug more effective. I think, some of Sid and Lou's work has shown that. I think, in other cases, you will see that the nutrition, itself, can be a very, very valuable therapeutic strategy, in and of itself, which Karen [inaudible 00:26:44] and Oliver, and others, have shown, as well. So, I think, it can be both, I think, it just depends on what's needed.

Kara Miller:

You both think that this area of cancer research is really promising. If you look out, five or 10 years, does food feel to you like the most exciting area? Are there other realms, that are also being explored, that you find like, "These are, also, really promising paths into cancer research"?

Siddhartha Mukherjee:

I think, that immunotherapy showed us something very important. And again, let me emphasize this. What we learned from immunotherapy against cancer, using the immune system against cancer, is that, you didn't need, necessarily, to sequence every tumor because the immune system was largely agnostic to what sequences, what genetic mutations, the tumor had. The immune system reacted to the changes, the physiological changes, in the tumor, itself. Things that didn't have to do with whether it had a mutation in KRAS, or DNMT3A, or whatever it might be.

Siddhartha Mukherjee:

I think, more and more, we are moving away from a time, in which we are saying to ourselves, "Yes. Precision medicine is important, but precision medicine is not the sequencing of tumors. It's something much broader. It is understanding the physiology of the tumor. What does it depend on?" One tumor might depend on its capacity to draw out blood vessels. Another tumor might depend very highly on histidine. Yet, another tumor might depend very highly on glucose metabolism. And so, the way I see, moving forward, is really understanding precision medicine, not as what I call sequencing medicine. And moving forward, in a way that we understand precision medicine, as a mechanism, to understand the brain of the tumor, the mind of the tumor, the physiology of the tumor, and using that as a mechanism. And, of course, nutrition is absolutely central to that idea.

Kara Miller:

Anand, do you think of what Faeth will provide to patients, as being like when you go on certain diets, all your meals are prepackaged and sent to you? Do you see that as being the thing that you give to patients?

Anand Parikh:

Yeah. I think, what Faeth does and delivers to patients is a tripartite approach. What we do is, we have precision nutrition, we have drugs, and we have software, and we wrap them together, in that unified package.

Kara Miller:

Okay.

Anand Parikh:

So we do all of them. We make sure that the drugs we're providing work with the precision nutrition, as well, and that they're both optimized for each other. But that's what I anticipate, that these patients will be getting from Faeth.

Kara Miller:

Okay. Do you think, because there's a big piece of this that's food and, maybe, in some cases, for some people, it's just a food thing, could this be cheaper than other treatments? Because one of the real problems we've seen with cancer drugs, especially in recent years, is, they're just phenomenally expensive.

Anand Parikh:

I think, unfortunate... So I hope that they can be cheaper.

Kara Miller:

Okay.

Anand Parikh:

I think, in manufacturing, because we are actually manufacturing food, to a degree, they will be more expensive. Because manufacturing each additional pill is pennies, manufacturing a meal is not. But I do think that a lot of that will go to the FDA. The overwhelming cost in drug development is in the clinical development of the drug, it's not actually in the manufacturing. It's mostly in all of running the trials, the regulatory hoopla, and all of that stuff.

Kara Miller:

Okay.

Anand Parikh:

So I do think that, in the future, with this treatment modality, if the FDA can start thinking creatively, that we could, then, be able to bring treatments to the entire globe, that are much, much cheaper than traditional treatments. I think, that's the other great thing about this approach, is that immunotherapy and other biologics are quite difficult to manufacture and administer, outside of sophisticated medical systems, in the US and Western Europe. I think, our intervention has the ability to be delivered in almost any setting, theoretically.

Kara Miller:

And then, a final question for both of you, which is, give me a sense of the timeline, here? How are you going to know when things work? If people are listening and they're very interested and they agree, "Yes. We need a different approach to cancer," what does that road ahead look like?

Siddhartha Mukherjee:

I mean, the timeline is now.

Kara Miller:

Okay.

Siddhartha Mukherjee:

I mean, we are already deploying. We are already making diets. We are already combining them with targeted therapies. The timeline is now. It'll keep being now. It'll keep being now, more. But Anand can answer more, but we are in the middle of trials.

Kara Miller:

Okay. Okay.

Anand Parikh:

That's right. I think. we're very, very excited about the trials that we have, ongoing. But I am hopeful that in the next 12 to 18 months, let's say, that we have data, in our hands, that can show the entire world, academic or otherwise, that precision nutrition can be this fourth pillar of cancer care, as Sid mentioned.

Kara Miller:

And will those results, in 12 to 18 months, allow you to move through the door, from trials to the wider world?

Anand Parikh:

They will allow us to move from, I would say, mid-size trials to really large trials, that will prove, definitively, the value proposition. Now, that's my assumption, but that will ultimately be, of course, up to the FDA.

Kara Miller:

And then, if everything were to go well, how long would it be, do you think, from now, that something would actually be on the market and a doctor somewhere could say, "Well, you have this cancer. And we're going to use Faeth"? How long would that be, do you think?

Anand Parikh:

I hate to hazard a guess at that because we're ready. The company is ready and ready to execute. It's really in the hands of the regulators, to a degree. So I'm hoping, in the next few years, the next two to three years, that we can kind of be at that point. But, ultimately, it will depend on what the regulators need to see, to believe.

Kara Miller:

Got it. Okay. Anand Parikh is a co-founder and the CEO of Faeth Therapeutics. Sid Mukherjee is also a co-founder of Faeth, as well as a Pulitzer Prize winning author, a physician, and an assistant professor of medicine, at Columbia. Thanks so much, to both of you.

Siddhartha Mukherjee:

Pleasure. My pleasure.

Anand Parikh:

Thank you, Kara.

Kara Miller:

And thanks, as always, to you, for joining us. Coming up next week,

Speaker 6:

We find that for successful venture capitalists, they, actually, aren't very swayed by charisma and passion, at all. They, actually, look for that rationality and a clear and well explained pitch, more than anything else. So I just would urge people to think about, even if they think they're not good at some of the skills, that they might think they need for startups, that doesn't mean they can't be successful.

Kara Miller:

Subscribe to Instigators of Change, wherever you get your podcasts, and leave us a review. Our show is produced by Matt Purdy. I'll talk to you next week.