Tricking Tumor Cells to Accept a Lethal Payload
How do you get a cancer cell to gobble up a ball of anticancer drugs and ferry it directly to the nucleus for a direct kill? It’s taken several decades to do it, but cancer researcher Mauro Ferrari says he and his team have finally figured out how to elude a tumor cell’s defenses. And he says the method works well on hard-to-target metastatic tumors, too — in mice, at least. They describe the work this week in the journal Nature Biotechnology.
Mauro Ferrari is President and CEO of the Houston Methodist Research Institute in Houston, Texas.
IRA FLATOW: This is Science Friday. I’m Ira Flatow. Later in the hour, we’re going to be talking about teaching climate change in the classroom. So if you’re a teacher who’s run up against challenges teaching climate change, we want to hear from you. Maybe you’re a student, also, who feels like you didn’t learn enough about it at school.
Well, in preparation for that segment, we want to hear from you. So give us a call, and we’ll get you up on the phone. 844-724-8255. That’s 844-724-8255. And you can, also, tweet us @scifri. S-C-I-F-R-I.
But first, how do you trick a cancer cell to commit suicide? This is not a knock-knock joke. It’s a really interesting situation. And it turns out it takes a lot of molecular gymnastics, which take advantage of the biochemical world in which a tumor sets up shop.
And my next guest started working on this problem 20 years ago– investigating how to use silicon nanoparticles to deliver a cancer drugs to tumors. And finally, after many years of toiling, he’s come up with a beautifully elegant system to make metastatic cancer cells gobble up poison, at least in mice.
And here to tell us about how it works is Mauro Ferrari. He’s the President and CEO of Houston Methodist Research Institute in Texas. Welcome to Science Friday, Dr. Ferrari.
MAURO FERRARI: Hi Ira, delighted to be here. It’s a great honor. I’ve been an avid and admired listener of yours for many years.
IRA FLATOW: Well, thank you. That’s very kind of you.
Now, one of the problems, historically, has been delivering the cancer drugs specifically to cancer cells where they can do the most damage. I don’t have to tell you that– localizing the effects. So how did you do it– figure it out?
MAURO FERRARI: OK, let’s put things in perspective first, if I may for a second. You know, the vast majority of deaths due to cancer are because of metastasis. This is when the cancer spreads from the primary organ to the lungs and the liver, primarily. That is the thing that we have not been able to– nobody has been able to cure yet, despite great advances in the last 20 25 years.
Those advances have been based on the notion that, perhaps, you can develop drugs that recognize cancer cells. And they trick with the machinery– they trick the machinery of the cancer cells that needed to die in a way that will save healthy cells. And that’s a good approach, but it does not take into account the other part.
The reason why cancer– metastatic cancer– can survive attacks is that it builds the different metastasis in the body– build these protective systems around themselves. Let’s call them biological barriers. They’re kind of like bunkers or kind of like protective walls around a medieval city. And there is many of them in different parts of the body to help them protect against attack by, of course, the different drugs.
So our approach has been let’s figure out a way to understand how these barriers work and design therapeutic agents that will be able to attack and break down these walls and penetrate across the bastards’ bunkers, if you will, one after the other. And there are several of them. There is many of them. So you need to have something that is, sequential in action, that crosses all these barriers one by one in the right order using different means. Just the drug is not enough, he’s got to have his vector with it.
If I can use an analogy– as good as our Navy SEALs are, you cannot ask them to jump off of the pier someplace on the East Coast and swim all the way to get the bad guys across the ocean. Right? They may be very good, but we need to be deployed in the right place. That is what we try to do.
IRA FLATOW: And so you used nanoparticles to– as a means of ferrying these, the SWAT team, in there?
MAURO FERRARI: Been there, done that. We started the nano program. I was at National Cancer Institute– it was my job to actually put it together some 15 years ago, and that is the largest program of nano medicine in the world yet. It’s done many good things.
But just the nanoparticle strategy does not work because the nanoparticles, per se– there are several barriers that they cannot penetrate across. So what we had to do? We had to come up with a way to deliver the pieces that can assemble a nanoparticle once you are inside of the walls, if you will, of the cancer city– to use the analogy, again.
So the trick is coming up with a way to inject in the general systemic circulation through an IV, for instance. Some particles, they can deploy the pieces across the barriers that protect the cancer from penetration from the bloodstream. And those pieces, once they are on the other side, somehow, figure out a way so that they can reassemble and be formed into a nanoparticle.
Once you are inside of the cancer, you want to be a nanoparticle because the cancer cells, at that point, recognize the nanoparticle as a package that they are familiar with. It looks like exosomes, which are the ways in which the little packages that cells use to talk to each other or to exchange information– to exchange materials.
So if you can make a nanoparticle once you are inside of the cancer that looks like an exosome, the cancer cell picks it up and says, this is like the spaghetti sauce that my mama used to send me every Saturday when I was in college. I see it showing up on my doorstep, so I pick it up, and bring it in.
And it is at that point– then, additional tricks have to come in so that the drug that is inside of the nanoparticle gets delivered to the right part of the cell– which is the next trick.
IRA FLATOW: So it goes– so you get this spaghetti sauce with the right kind of– right kind of part–
MAURO FERRARI: I am Italian, so I can say it.
IRA FLATOW: That’s OK. I’m going with this analogy. I like it. It’s one of my favorite things.
MAURO FERRARI: Good.
IRA FLATOW: It gets inside the cell, and then– so it self-assembles inside the cell, and then, it breaks the tumor.
MAURO FERRARI: It self-assembles inside of the cancer. Cancer is like a city. It’s got many, many different components. Some of those are cancer cells. Some of those are innocent bystander cells that are slayed by the cancer. So the cells– you need to form the particle inside of the cancer microenvironment.
But then, once the nanoparticle is formed– is recognized by the cancer cell– it’s brought inside of another set of walls– think Trojan horse for a moment. And at that point, what happens is that the cell has this fabulous way of transporting materials inside of them. It’s kind of like a railway system that is very directed.
And so you hop on the transport system, the internal railways of the cell, and you hitch a ride all the way to the nucleus, which is where you want to deliver your drug. And as you do that, you’re able to avoid– so another set of marvelous protective systems the cell’s have, what are called multidrug resistant pumps.
Imagine for a moment you are out on a boat, and it starts taking in water. So what you do– you get your bucket, and you get the water out to save the boat, right– and to save yourself. Cells do something similar. They have these little bucket brigades on the cell membrane so far away from the nucleus.
And if you hitch a ride because you are a nanoparticle– you hitch a ride on the transport system of the cell. You can make it to the nucleus– kind of like, think, Death Star, if you want. You get to the nucleus avoiding the pumping mechanisms. They’re on the outside of the cell. And that is the last barrier that you need to be able to avoid.
IRA FLATOW: So how successful have you been in actually killing the tumors in these mice using this–
MAURO FERRARI: It was so successful that when we saw it, we literally went back and did it again. We took another year to do all experiments again and another year to do all the experiments again before we actually published this in Nature Biotech.
IRA FLATOW: You cured half the mice in your experiments?
MAURO FERRARI: Cured– completely cured half of the mice that had the lung metastasis from triple negative breast cancer. And they’re completely cured. I mean, these guys live like their little sister littermates. So they never had cancer to start with.
And even the ones that ended up dying– extending their expected survival for the human equivalent of, say, four or five years. If you think about it to the way we clinically approve drugs, it is if they can show that there is a survival benefit of two, three weeks, maybe a month, maybe two months.
Now, even the ones that went poorly, we extended their lives four to five years. But half of them are completely cured.
IRA FLATOW: So you know, my listeners all want to know when they’re going to get this for themselves. Obviously, not anytime real soon because it needs to go through trials?
MAURO FERRARI: Oh, no, no, no. Thanks– of course, they need to go through trials, but this is a very important point. Thanks for asking. Usually, it takes a huge time between discovery and deployment in the clinical– even to the start of clinical trials. But we used to [INAUDIBLE] because our philosophy has been exactly that, of not only generating new science, but also building inside of our institution the infrastructure that can move things through clinical trials in the most safest and most expeditious way so that we can get through clinical trials quickly.
So I already have– long story short. I already have good manufacturing practice facilities for this drug. I am in the process of doing GIP testing. These are a little bit technical, but the long and the short of it is that within 12 months to 18 months, if the FDA will allow it, we are planning to start clinical trials.
That is our target, which has got to be some sort of a land-speed record– world-speed record, here. We have done everything pari passu because we were confident that we would get to this point.
IRA FLATOW: You’ve got to feel very proud of yourself. You have decades of work on this.
MAURO FERRARI: Pride, pride. No, no. Pride has got nothing to do with this. We’ve got to focus on service– making sure that we have the– that we keep thinking of our ultimate objective is our patients. So there is no room for pride. There is, of course, pride in my collaborators and my co-workers. They are great people.
IRA FLATOW: But you never got frustrated in all these years?
MAURO FERRARI: Frustration is the middle name. Right? Of course, these things that– most of the time, science, of course– especially in this domain, most of the time, science doesn’t work. It’s like playing basketball. You’re always 20 points behind. That doesn’t mean you’re never going to win the game, but you have to have enough heart to keep on playing for 20 years, always being 20 points behind thinking that, somehow, on the last day, whenever that is, there’s going to be an opportunity to get ahead and to bring cures to people that need it.
IRA FLATOW: So what kept you going? What kept you playing that game 20 points behind?
MAURO FERRARI: That’s a good question. It’s the notion of– once you realize that there is something that you can do for people that are in such difficult situation– and then there’s these tragedies– once you realize there is something you can do, it becomes a mission. Right? It becomes something that you have to do. It’s an ethical responsibility.
And you cannot focus about yourself and your things. If you do that, then things fall apart. Luckily, I have a great environment around me. I have Haifa Shen, my collaborator, and all these other great people that worked on this, and you kind of help each other out. Right? That’s the way to do this.
I tried to recruit with– this is what we call this BLT principle– people that are B, best; people that L, I like; and people that T, I trust. And if you have BLT around you– like in a good sandwich.
IRA FLATOW: We have that here at Science Friday. I know exactly what you’re talking about. But you know, I wish you the greatest of luck. I know how difficult it is to bring mouse success to humans, but I think, maybe you can do it. And I want to thank you for taking time to be with us today. And good luck to you, Dr. Ferrari.
MAURO FERRARI: Thank you very much for having me.
IRA FLATOW: Mauro Ferrari is president and CEO of the Houston Methodist Research Institute in Texas.