The Biggest Challenge in Medicine with Dr. Linda Malkas

Why have we not found the cure for cancer yet? Neil deGrasse Tyson, Chuck Nice, and Gary O’Reilly explore paradigm shifts in cancer treatment, molecular biology, and a promising new cancer drug AOH1996 with City of Hope cancer researcher Dr. Linda Malkas.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Neil deGrasse Tyson?

  Today on StarTalk Special Edition, we learn about a hopeful new direction of cancer treatments and how they work. Could we one day rid humanity of this terrible multifaceted disease? Up next on StarTalk.

• 0:19Neil deGrasse Tyson?

  Welcome to StarTalk, your place in the universe where science and pop culture collide. StarTalk begins right now. This is StarTalk. Neil deGrasse Tyson, your personal astrophysicist, serving as your host. Today it's special edition. I got with me my special edition co-host, Gary O'Reilly. Gary.

• 0:46Speaker 01

  Hi Neil.

• 0:47Neil deGrasse Tyson?

  Yeah, former soccer pro and sports commentator. Also got Chuck Nice. Chuck, always good to have you, man. Hey Neil. So today, we're taking up the top, very serious topic, the emperor of all maladies, cancer. Oh my gosh. Gary, what did you put together for today?

• 1:02Speaker 01

  Uh, well, finding a successful treatment for cancer has long been one of medical science's biggest challenges, if not the biggest challenge. So, you know, with variable results and some rather nasty side effects. But there was one particular cancer researcher at City of Hope Cancer Research and Treatment Center in Los Angeles, decided, as she says, "Follow the science." And now we are looking at the possibility of a treatment that takes out the cancerous tumor, but leaves the healthy cells around it intact. I mean, this, yeah, wow. This is the kind of science that really could change people's lives. And by the way, our guest once dreamed of being an astronaut. So, uh, Neil, yes, if you would like to introduce

• 1:46Speaker 01

  our guest, I think we're gonna have an interesting show.

• 1:49Neil deGrasse Tyson?

  Okay, I'll introduce anyone who ever dreamed of becoming an astronaut. Linda Malkas, PhD. Linda, welcome to StarTalk.

• 1:58Speaker 02

  Thank you so much. It's such an honor to be here.

• 2:01Neil deGrasse Tyson?

  You're Associate Chair and Professor in the Department of Molecular and Cellular Biology at the City of Hope Cancer Research and Treatment Center. So I'm just glad places like that exist in this world. And you have clinical expertise in molecular diagnostics and experimental therapeutics. So it sounds like you're all up in this.

• 2:25Neil deGrasse Tyson?

  Uh, and so just welcome and tell us about cancer. Like what? All I I have basic understanding of cancer. What what Chuck? What do you ask?

• 2:37Chuck Nice?

  I was gonna say that sounds like the worst bedtime story request ever.

• 2:43Neil deGrasse Tyson?

  Read to me about.

• 2:44Chuck Nice?

  Tell me about cancer.

• 2:48Neil deGrasse Tyson?

  So so cancer is hard to treat as I understand it because it the cells look just like your cells. So anything would that would kill a cancer cell is going to kill your cell. And that's the beginning and end of what I know about cancer, basically. So what what can you add to that? And what can you tell us about the new treatment?

• 3:06Speaker 02

  Well, actually, you got a really good start with this in that the that cancer. Cancer, I guess, you know, in in my opinion, is really kind of a way the body turning on itself. And cancer is like, you know, being that I you already know I'm a, you know, like a science fiction geek. Uh, so alien, you know, if you think of the movie Aliens, you know, you can think of cancer as, you know, the most perfect predator, you know, it it really is it. And it's why it's so hard to treat because it looks like us. It's our own body. It knows all our own tricks, you know, how, you know, it's our processes, which it uses against us.

• 3:51Speaker 02

  And then cancer also has this ability uh to constantly evolve. It's actually a very scary predator. It really is. Uh, and that's why it's so very, very hard to treat because it's constantly changing itself. It is such a weird entity. Uh, that's how I, you know, and I used to, when I was first studying, you know, I would really look at it as like a, you know, it's a cell, you know, but it's almost like a living entity. It is, you know, because it it can evolve. It has, uh, you know, normal cells. They have these, you know, if you think about it every day. And I want to congratulate you all. You're all cancer survivors, every one of us, including myself.

• 4:34Speaker 02

  Every day since before we were born, we make at least eight cancer cells. And our immune systems take them out. So we're constantly making.

• 4:42Neil deGrasse Tyson?

  With eight cells per per.

• 4:46Speaker 02

  Day.

• 4:47Neil deGrasse Tyson?

  Per day. Every day.

• 4:48Speaker 02

  Per day.

• 4:49Neil deGrasse Tyson?

  Okay.

• 4:49Speaker 02

  Per day.

• 4:50Neil deGrasse Tyson?

  Every day.

• 4:50Speaker 02

  Okay, so we're making at least eight cancer cells every day. And your immune system is constantly surveilling and taking them out. We also have these other wonderful processes in our cells. We are constantly making DNA damage. Just the act of eating and metabolizing food, you're actually making, you know, free radicals, which are attached, you know, attacking your DNA. We have these wonderful DNA repair systems that go in and just clean it all up. And, you know, the cells divide and, you know, and we're rather a miracle that we were here and there and not giant tumors as it is.

• 5:34Speaker 02

  But cancer cells, it's true, it's true.

• 5:38Neil deGrasse Tyson?

  It's a miracle. It's a miracle that we are ourselves and not just tumors walking around.

• 5:43Speaker 02

  I'm telling you.

• 5:44Neil deGrasse Tyson?

  In civilization.

• 5:44Speaker 02

  Tumors with eyes, you know, so.

• 5:48Neil deGrasse Tyson?

  That's a sci fi story.

• 5:50Speaker 02

  I'm glad I just scared myself. So, you know, you have these cancer, so you have cells, these, you know, they become cancer cells, you know, they're started by DNA damage, okay, or a mutation. I mean, that's the heart of what cancer is, a change to your genome, change to your DNA. But what happens with cancer cells is they go on to make DNA, they're DNA damage to themselves, they continue, it's called constitutive replication stress. They are continually damaging themselves.

• 6:29Speaker 02

  And you think about that, you go, why would a cell continue to make damage? It doesn't make sense. It's like, you know, why are you continually mutating your own genome? But that is, the way I look at it and others is actually it's almost an evolutionary mechanism for them. Like I said, you know, every day we're making eight cancer cells. We have this incredible immune system that's constantly surveilling and, you know, taking them out. So for a cancer cell to survive, it needs to constantly change itself so that it can avoid the surveillance system.

• 7:11Chuck Nice?

  It sounds eerily like a virus, the way that you explain it.

• 7:16Neil deGrasse Tyson?

  It's diabolical.

• 7:17Speaker 02

  Yeah, yeah, and you know, it's interesting that you mentioned viruses because you know, it's very interesting because you know, there is been thinking for a long time, you know, that ways to even treat some forms of cancer could, you know, could we use things that, you know, we use to target viruses, we use them for cancer. So, uh, it's, it's a, it's a scary thing. I don't want to scare your audience, but.

• 7:47Neil deGrasse Tyson?

  You already have. It's too late for that.

• 7:51Speaker 02

  So good thing, so you know, practice good health.

• 7:54Neil deGrasse Tyson?

  No, I can't get walking tumors with eyes out of my hair because of that. So what is, what is, what is this treatment that has 1996 in the title? What is this?

• 8:07Speaker 02

  So if you look inside the human cell, there's nucleus, right? You know, I always call the nucleus like the house of DNA. Okay. So in the house of DNA, you know, the human self harbors three feet of DNA inside the nucleus of every cell.

• 8:21Neil deGrasse Tyson?

  If you uncoiled it.

• 8:22Speaker 02

  Uncoiled it all out and stretched it out linearly, three feet of DNA is shoved into something we can't even see, all right?

• 8:30Neil deGrasse Tyson?

  You know, if you took all the DNA of every cell and tied it end to end, that the person will die.

• 8:36Speaker 02

  Well, probably, but also if you took all the DNA out of one human and stretched it out in his face, it goes beyond the sun.

• 8:45Chuck Nice?

  Wow, just from one human?

• 8:48Speaker 02

  Yeah, that's how much genetic information we harbor. That's how much genetic information we harbor. We are amazing machines.

• 8:56Neil deGrasse Tyson?

  And the person dies in that case, too.

• 8:58Speaker 02

  Well, yeah, especially if you get close to the sun. So, so it's our gut, you know, we're like a tube within a tube. So your gut turns over like every two to three days. So there's a lot of cell division that goes on in your gut. And every time your gut cells have, or any cell in the human body has to divide, what you do is the mother cell has to make a whole new complement. So that's another three feet of DNA stuffed inside of one nucleus. And then it's those two cells in the DNA are divided out. So I got really interested, how does a human cell replicate its DNA in such a confined space?

• 9:42Speaker 02

  And inside of like eight hours, it makes that. There isn't a human machine that we have invented that can actually do anything near this with such incredible fidelity. So I got involved in studying DNA replication complexes. And so that was my first foray into molecular biology is actually understanding the DNA replication process. And then, you know, as an independent investigator, I started reading about cancer. And cancer, you know, is a disease of DNA damage. That's really what cancer is.

• 10:22Chuck Nice?

  The crime scene of replication?

• 10:24Speaker 02

  Yeah. And here, here, like Agatha Christie, here she goes. So I go and I say, you know, I'm like the mother of replication complexes. I can make, I literally can isolate from a human cell replication complex, put it into a test tube, offer a DNA, and it would make DNA just like, you know, inside the cell. So I said, gee, I wonder if this complex is different in cancer cells versus normal cells? And I won't go into the glory details, but the bottom line was, yes, it was different in cancer cells. Cancer cells corrupt the DNA replication apparatus so that it allows a sprinkling

• 11:08Speaker 02

  of DNA damage every time it makes it. So, so actually you can almost think of the daughter cells of a mother cancer cells are different from its own mother. That's how it changes. So since I knew a lot of the proteins that were inside of this replication machine, I started looking through who was different. And we found one protein, which I didn't think would it be the protein. I thought it was going to be one of the cool DNA polymerases, you know? But it wasn't. It was a protein called proliferating cell nuclear antigen or PCNA.

• 11:42Speaker 02

  Now, way back when, when we first found this altered form of PCNA,

• 11:50Speaker 02

  you know, people would never have looked at, they always think it was like this, so it's called a sliding clamp protein. And I liken it, okay, like if you think of DNA as like a shower curtain rod, PCNA is kind of like your shower curtain ring. So, so PCNA is a sliding clamp protein in the circles, DNA. And what it does, it tethers three other molecules that have to work at DNA and allows them to process and do whatever it is that they have to do. Now, the cool thing about PCNA, now you're getting me, I hope I'm not boring you guys, because this is like,

• 12:27Neil deGrasse Tyson?

  Go on.

• 12:28Speaker 02

  This is it, okay?

• 12:29Neil deGrasse Tyson?

  Go for it. Bring it on.

• 12:32Speaker 02

  Okay, PCNA, okay, interacts with at least 200 other proteins in the human cell. It has by protein, protein interaction. So, we found that PCNA was different in cancer cells compared to normal cells. And that that difference in PCNA correlated now with this funky replication act, right? I mean, you know, technically, we found a new molecular target, this PCNA that's different in cancer cells. And it's not changed in the genome, it's not changed because of RNA. If I was to develop a drug to that PCNA,

• 13:14Speaker 02

  to the form that's only in the cancer cell and not in the normal cell, several things come from this. One, I would, I would target and knock out only the cancer cell, because that drug would only be effective inside the cancer cell to kill the cancer cell. But it would also be super effective, because it's not just attacking one protein, it's taking out an entire network.

• 13:41Speaker 02

  Of 200 protein functions inside of the cancer cell, while leaving that same network in place in the normal cell. That is the heart of what AOH 1996 is.

• 13:54Neil deGrasse Tyson?

  So this was, this was a race to find something different about the cancer cell that had eluded people.

• 14:00Speaker 02

  It totally is. It's, it's, uh, it has so many novel features to it. I'll be very honest, when we first found it, you know, and, you know, everybody wondered, how come it takes so long to do, you know, cancer, why can't they do these things fast?

• 14:16Neil deGrasse Tyson?

  Is that what we sound like to you?

• 14:17Speaker 02

  No, that's, that's a great. A lot of flying, I'm on a lot of airplanes and I'll sit next to people on airplanes. This has to happen to you too, but I'll sit on airplanes and I'll tell people what I, you know, I am a cancer researcher. I get a couple of different things. One is, you know, they already have the cure for cancer. They're just holding it back, you know?

• 14:37Chuck Nice?

  Oh God, really? Gotta love those people. Yeah. You know, they make so much money off of treating cancer. They can't cure it. And I'm just like, can you imagine how much money they would make off of a cure?

• 14:51Speaker 02

  That's what I always say. So then the other thing I get is, um, you know, why does it take so long? Because, you know, finding a target, moving it forward, you know, the, this target was so different. I actually went to a very large pharma company, uh, way back when. So this is when I first found it and I say, hey, I found this great molecular target. Can you help me make a drug to it? And they, uh, they said it was undruggable, that there was no way.

• 15:21Neil deGrasse Tyson?

  Why, why was PCNA undruggable then? What was it about that particular protein that made it?

• 15:26Speaker 02

  It's changing. There's dogma, okay? There's some dogma in the field and dogma was you only to, uh, uh, make a drug against an enzyme. Uh, and so it was quite crushing to me when I went to this very large pharma company and I danced for them. You know, I took all, I talked about replication conflicts. I was dancing for them and saying, this is a great target. And they're very kind. They were listening to me and they said, undruggable. You'll never be able to make a drug to this. It's, it's involved in protein, protein interactions. It's an enzosorted protein region. It's impossible.

• 16:05Speaker 02

  And I just, you know, when I left that place, you know, I said, oh my God, how could I have been such a, how could I have been so, you know, but by the time I made the parking lot of that place, I was like, I'll be damned. I'm gonna, I'm gonna try to figure this out. Wait, don't, wait, don't tell me you found a solution just to spite somebody. No, no, actually, I, I did it. No, no. Whatever the motivation is, I guess. No, no, I made a promise to a family that I was going to go and try to do something. Okay. About cancer.

• 16:39Chuck Nice?

  Oh, wow.

• 16:40Speaker 02

  So there's an underlying heart issue here. Okay. There's a noble, there's a noble cause. There is a very noble cause.

• 16:47Chuck Nice?

  Yes, spite, spite sells better, though. Let me just tell you something. When, when we make the movie, when we make the Linda Malkas movie about, you know, the, the, the, the, the treatment and the, the, the cure of these certain types of cancers, um, the spite angle is what we're gonna go with.

• 17:05Speaker 02

  You know, spite is great, you know, spite, spite is great fuel.

• 17:10Chuck Nice?

  Yeah.

• 17:11Speaker 02

  But it won't hold you for long term.

• 17:13Chuck Nice?

  That's a very good point.

• 17:14Speaker 02

  Agreed.

• 17:14Chuck Nice?

  That, that, that really is a really good point.

• 17:16Speaker 02

  You know, it really, you can only go so far because you, you know, you just run out of fuel. But it's a heart issue and it's a promise. That's something else.

• 17:39Speaker 01

  So, okay, I'm gonna dub you the queen of different thinking, just for the moment. Was there other different thinking that had to follow your initial thought process that obviously was different to everyone else's that led you to AOH 1996 and its efficacy?

• 17:55Speaker 02

  Well, so, so there is this, so you think about how this drug is working. It is very different. Okay. It wasn't an enzyme targeting an enzyme. And my thinking was, you know, I speak a lot in analogy, just because it is new concept. So always, one of the things, one of my academic positions, I was in Indiana, the Indiana University School of Medicine, and I found that one of the ways that she shut down most of the air traffic in the United States, and she sent a snowstorm into O'Hare, and you shut down all those routes. So PCNA is a terminal, okay, it's a hub, it's an okay, and you're shutting down 200 flights out.

• 18:39Speaker 02

  So literally, what I'm trying to do is build a snowstorm.

• 18:43Chuck Nice?

  That's brilliant, because that, going back, going back, that's going back to this sliding clamp that you talk about, these proteins all being connected. And so what you're doing is, you're coming in and you're saying, I'm not going to treat this, what I'm going to do is shut down the system inside of the system.

• 18:59Speaker 02

  Shut down the whole network, shut down the whole, the whole thing. So that was really different. And as, as luck would have it, this place called City of Hope called me out of the blue and asked me if I would be an external advisor for them to come in and review their research program. And so when I went there, I had, I was blown away because they had put together this incredible apparatus, which I hadn't seen inside of an academic institution before, where they had put together all the people, the resources, and the facilities for actually taking an idea off a lab bench and moving it to the clinic.

• 19:43Speaker 02

  And I was like, this is where I gotta go. So now PCNA. So I moved to City of Hope, and they're wonderful, I'm got with all these, these great minds, right? But I still had to do a lot of molecular biology, even to get them to be able to work on what I needed to do. And what I had to do was figure out where on the PCNA molecule was the business part for the cancer. And so what I did was, I made it, I got the PCNA gene out, you know, and we made mutations through PCNA. And we made antibodies, all kinds of things, and we were actually able to define

• 20:26Speaker 02

  a small domain of about ten amino acids, which was the difference between cancer and normal. Once I had that address on the protein, so you know, every protein is so beautiful. Each one has its own crystal structure. You know, if you look at the crystal structure, they're like, every protein's like its own fingerprint. So I found on this big protein, this little bitty address. But it had, that address had made, formed a pocket inside of the molecule. And, uh, once I had that pocket,

• 21:08Speaker 02

  that's when I could start screening for molecules. And we screened through 6.5 million molecules that would sit inside.

• 21:17Neil deGrasse Tyson?

  Are these humans, or is it some form of AI doing this?

• 21:21Speaker 02

  It's a form of AI. So it's, it's, you know, you use these gigantic, so this, this is so cool. I mean, this is called virtual screening. So they have, you know, these fantastic computers, you know, with, uh, you know, these databases of, of molecules, just, and they're like from everything, from trees and mushrooms and, you know, from everything, any kind of structure. Uh, so the 6.5 million molecules. And you take your protein, that, that 3D form of your protein, and I got that little pocket sitting inside that protein. And you take that structure in that little pocket, and you stick it in the computer,

• 22:05Speaker 02

  and the computer goes 6.5 million times this way.

• 22:09Chuck Nice?

  Right, to see what puzzles together.

• 22:12Speaker 02

  Right. And it came up with 53. Fifty-three out of 6.5 million.

• 22:20Speaker 02

  And we took them home. And we tested 53 compounds on normal versus cancer cells. And of the 53 compounds, we found five that killed the cancer cells and left the normal cells alone.

• 22:37Neil deGrasse Tyson?

  And left the other cells.

• 22:38Speaker 02

  And it was like, oh my God, but that doesn't mean anything. It's on a lab bench. How do I bring that forward? Now from a lab bench?

• 22:50Neil deGrasse Tyson?

  And, and has that, and the work has been duplicated?

• 22:54Speaker 02

  Yeah, I mean, this is, you know, actually, you know, we've moved, uh, so then it becomes this incredible process of, you know, having that, and what they call it a hit. So of those five molecules, we picked one. Very unique structure, nothing looked like it chemically. And we moved it slowly forward through the process. So, um, and it became AOH 1996. It's in clinical trial now. It's in a phase one trial.

• 23:26Neil deGrasse Tyson?

  With humans? Is phase, is phase one with humans?

• 23:29Speaker 02

  In humans.

• 23:30Neil deGrasse Tyson?

  What phases with, with, with other animals?

• 23:32Speaker 02

  Okay, so.

• 23:33Neil deGrasse Tyson?

  Is that, is that one of the phases?

• 23:34Speaker 02

  Yeah, so the workup to get to the FDA, you have to do testing in animals. Uh, we did it in mice and dogs. Um, and the beautiful part of it, of all those, that testing was, it did not show toxicity. We never found the maximum tolerated dose. The animals are very happy on it. I mean, you know, they're, they're, they show no, they eat, uh, they show no neurological problems. Um, and in tumor models, you know, animal tumor models, we show that we could inhibit, uh, tumor growth. And with all that data, you go to

• 24:14Speaker 02

  the FDA, and then they granted permission now for the phase one trial. So we have patients that have been enrolled in the phase one trial. Uh, and the phase one trial, so there's three levels of trialing, uh, to move something to, that, you know, it can be used in the clinic. Phase one is a toxicity trial. You know, how, what, can we find the maximum tolerated dose in humans? I have a strong suspicion we won't. Um, and then you go on to now efficacy trials. Those are called phase two trials, where, you know, do you see any effect in, on, on a, a person with tumor? And then phase three are these large trials,

• 24:59Speaker 02

  you know, over different populations, things like that.

• 25:04Speaker 01

  You describe cancer as a molecular signature disease. I can say that, but I'm not quite sure I'm anywhere near qualified to explain what that means. So would you, in terms that I might understand, what that actually means? Because you don't see it as singular, you see it as multiple diseases, don't you?

• 25:24Speaker 02

  Yes, so, you know, when I was learning, you know, I was training, cancer was really thought as like one thing. You know, you had breast cancer, you had lung cancer, you had prostate cancer, you had, you know, whatever cancer, it was one type, right? And I used to work with a wonderful breast cancer oncologist out in Indiana. And he said it would drive him crazy. He said, "Linda, I'd have two women who come in with breast cancer in my practice, and everything about them is the same.

• 26:07Speaker 02

  You know, they grew up on the same street, they have, you know, they have the same number of children. Everything I could measure about them was the same." He said, "I would put them on protocol, and one would respond beautifully, and one would die. And there was no way to tell the difference." That was our thinking for so long, that, you know, cancer was one thing, and a cancer type was one thing. We have, that has totally been radically changed, because cancer is probably as individual as your fingerprint.

• 26:43Chuck Nice?

  Well, cancer has it affects the individual.

• 26:46Speaker 02

  Yes, your tumor.

• 26:47Chuck Nice?

  Yeah, that makes sense.

• 26:49Speaker 02

  So you think about your tumor now. Your tumor has its molecular signature.

• 26:55Speaker 02

  You know, the thing that's that, you know, there's a lot of unique features. That's why, you know, this molecular signature part of cancer is such a, a, a huge breakthrough. You know, where they call it precision medicine now, or moving towards precision medicine. In that-

• 27:16Neil deGrasse Tyson?

  Is that the same thing as, as designer medicine?

• 27:19Speaker 02

  You're getting there. Seriously, you're getting there.

• 27:22Neil deGrasse Tyson?

  Okay.

• 27:22Speaker 02

  Uh, so, you know, if you, and, and if you can think the two, like we, the other thing with, that we had very myopic vision was that tumor was all by itself, but you also have to recognize that the tumor is sitting inside of a host. So there's a, the environment around a tumor is going to influence cancer activity just as much as the tumor itself. So-

• 27:48Neil deGrasse Tyson?

  If I'm not serving dinner at home, I don't like being called a host. There's something about that. Well, yeah.

• 27:55Chuck Nice?

  I'm, I'm, I'm cool with it as long as there's, as long as there's not a parasite involved, I'm all right with it.

• 28:00Neil deGrasse Tyson?

  That's what says my whole point.

• 28:01Speaker 02

  Uh, I'll tell you, cancer is a parasite. It just hasn't figured out how to kill hosts. It is a parasite.

• 28:07Neil deGrasse Tyson?

  Right.

• 28:07Speaker 02

  I mean, cancer is a parasite. So now a person comes in to clinic. You have their genome read and you can actually figure out, we're moving to this. We already do it in some cancers. But you look at their molecular signature and you're starting to say, oh, well, you know, this drug works better in this place.

• 28:30Neil deGrasse Tyson?

  Right.

• 28:30Speaker 02

  And you know, and even if the drug-

• 28:32Neil deGrasse Tyson?

  Genomically targeted.

• 28:33Speaker 02

  Yeah, even if the drug was found in lung cancer. But a woman could come into the clinic with breast cancer with the molecular signature of that, of the tumor that would really work well with a lung drug. I mean, it's really amazing. We are really in a very, very different kind of time and a revolution in time and thinking.

• 28:57Neil deGrasse Tyson?

  But so what is the evidence that one kind of cancer migrated from one organ to another?

• 29:05Speaker 02

  Okay, though that's

• 29:06Neil deGrasse Tyson?

  Because many women with breast cancer die of brain cancer.

• 29:09Speaker 02

  I don't want you to get confused. I don't want you to get confused.

• 29:11Neil deGrasse Tyson?

  Yeah, I don't want to.

• 29:12Speaker 02

  Yeah, so there's actually two things going on. One is metastasis. You know, where, you know, like a woman has a breast cancer and they will likely metastasize to bone or brain. I mean, it's kind of like it has a homing device that will go there. It likes that environment, you know? The other thing that I was, but I want to stress is the molecular signature is not about metastasis. Sometimes the things that are helpful to a tumor to grow, whether it's breast or lung, are the switching on or off of particular genes.

• 29:49Speaker 02

  That, so that is a molecular signature that could help us potentially either use current therapies or make new therapies for. That's a, that's a, you know, base molecular signature. Metastasis is a whole nother animal.

• 30:25Chuck Nice?

  So can I ask you about when we first started? So you said that we produce eight cancer cells per day. How does this treatment differ in our body's eradication of those eight cells? And why don't we just try to replicate what the body, so you have this antigen? Is our body making an antibody that actually just kills these eight cells? Exactly how is the body killing the eight cells? And why aren't we trying to replicate that?

• 30:57Speaker 02

  So it's good that you bring these things up. So that, you know, one of the big arms or areas of research that is going on is immunotherapy. Right? It's like harnessing the power of the immune system. And so you have, you know, they call them CAR T cells therapy. There are immune checkpoint therapies. Huge. This is a amazing question. I mean, there, you know, obviously in a fully functional person, our immune system is keeping things in, where they're keeping cancer in balance. You know, you're in check. They're keeping it in check.

• 31:38Speaker 02

  Whatever reason, you know, we become out of balance, you know, or you're exposed to some environmental cause. You produce, you, you can't, the body doesn't maintain that balance anymore. So there are wonderful arms of research, some of it's going on at City of Hope, very, very exciting, where they are exploiting now or trying to understand how to better harness the immune system. We know a lot about it, but we're still in the very early stage and it's such a powerful weapon. But you know, the thing is, but I have to go back.

• 32:19Speaker 02

  Cancer constantly is figuring its way around things that we throw at it. You know, way back when, when I was training, everybody said, you know, we're going to find the cancer gene, the cancer gene. Turns out there's lots of cancer genes. We were going to, and then there was something called tumor suppressors on top of it. I do not believe we will ever have a single therapy. What we will have is, and I believe AOH 1996 is going to serve as one of the agents in an arsenal. We already have an arsenal, but the object is, was using precision medicine.

• 33:04Speaker 02

  That we are able to turn cancer from a critical disease into now a managed disease and we're moving towards that. I actually have a friend who had breast cancer and she never went into remission. She lived for 12 years.

• 33:22Chuck Nice?

  Oh, that's kind of like prostate cancer.

• 33:24Speaker 02

  Totally.

• 33:24Chuck Nice?

  Most men, most men die with prostate cancer because it's so, it's such a slow growing cancer that sometimes it's like, well, we keep an eye on it. You know, there's no need to do anything invasive uh because you'll be dead before it kills you.

• 33:37Speaker 02

  Yeah, but it's a very painful cancer for men. It really is.

• 33:40Chuck Nice?

  Oh.

• 33:41Speaker 02

  Yeah.

• 33:41Chuck Nice?

  I did not know that.

• 33:43Speaker 02

  I know, actually in some, you know, if it, you know, if it progresses for them.

• 33:48Chuck Nice?

  Yeah.

• 33:49Speaker 02

  Yeah, yeah.

• 33:50Speaker 01

  AOH 1996 is administered as a pill.

• 33:54Speaker 02

  Yes, twice a day.

• 33:56Speaker 01

  Why, why, why a pill? Why, why, why isn't it injectable or some other form of approach?

• 34:04Speaker 02

  Okay, so why, why a pill? Uh, I wanted to make it easier on the patient. You know, as opposed to them having to be hooked up to infusion, but also based on the uh, the chemistry of the drug, it has a half-life of about five hours. And so in order to keep the drug present all the time, it needs to be administered twice a day. So it didn't, you know, patient isn't going to come in and be hooked up to an infusion, you know, all the time. So uh, so it's a continued, you know, the patient comes in.

• 34:46Speaker 02

  Uh, they are, you know, our phase one patients come in, they are, you know, checked for, you know, certain how they're doing and everything. And then uh, they're given their pills and they, they go home and they, they take it. And so they take it twice a day.

• 35:04Neil deGrasse Tyson?

  So Linda, I heard you use the term half-life. Is that in the way we would use that term in physics?

• 35:09Speaker 02

  Yeah.

• 35:10Neil deGrasse Tyson?

  Where after a certain amount of time, is half of the thing that matters that's still active?

• 35:16Speaker 02

  Yes, absolutely, absolutely. So the body, you know, the drug is metabolized, you know, eventually.

• 35:24Neil deGrasse Tyson?

  Metabolized, that's what it's about.

• 35:25Speaker 02

  Yeah, it has a half-life metabolism, yeah.

• 35:28Neil deGrasse Tyson?

  So after five hours, there's half of the drug, and after another five hours, half of what that was.

• 35:34Speaker 02

  Right.

• 35:35Neil deGrasse Tyson?

  Half of the half, and so then you gotta pick it back up with another dose.

• 35:39Speaker 02

  Right, right.

• 35:40Neil deGrasse Tyson?

  So, I get it, okay.

• 35:41Speaker 02

  Yeah, that's like, you know, like anybody taking antibiotics, you know, some people have to take it three times a day, or twice a day. It has to do with maintaining a drug level.

• 35:52Neil deGrasse Tyson?

  I know, I understand it precisely with that terminology, but I've never seen the term "half-life" on a bottle of drugs.

• 36:00Chuck Nice?

  They should put it on there.

• 36:01Speaker 02

  Those are the things behind the label.

• 36:04Chuck Nice?

  Yeah, they should put it on there because it's so important, like when you said antibiotics, a lot of people screw up their antibiotics because they're not taking them when they're supposed to take them, or they don't finish them, and it's so important that you do that because of that reason.

• 36:18Neil deGrasse Tyson?

  The half-life, it might make it a little more urgent to them.

• 36:21Chuck Nice?

  It might make it more urgent if you said like...

• 36:23Neil deGrasse Tyson?

  Yeah.

• 36:24Speaker 02

  Any drugs, you know, if they say, you know, "take it every eight hours," it all has to do with the drug half-life.

• 36:30Chuck Nice?

  Right.

• 36:31Neil deGrasse Tyson?

  Yeah, yeah, yeah.

• 36:32Speaker 02

  Yeah.

• 36:32Chuck Nice?

  That's a good thing to know.

• 36:33Neil deGrasse Tyson?

  I will henceforth think of it in those terms.

• 36:36Chuck Nice?

  Yeah?

• 36:36Speaker 02

  Yeah.

• 36:37Neil deGrasse Tyson?

  It's the half-life of my aspirin, right.

• 36:39Speaker 02

  Yeah, so if you like to have...

• 36:40Chuck Nice?

  I'll tell you the half, I'll tell you the half-life of aspirin children.

• 36:47Speaker 01

  You said AOH 1996 would most likely be most effective as a combination therapy.

• 36:55Speaker 01

  Is that going to be beneficial for cancer resistance? As opposed to like a single pathway therapy?

• 37:04Speaker 02

  It's actually a wonderful question, Gary. Thank you. So one of the problems with cancer, it's a pain in the butt. Remember, it's this evolutionary thing going on with cancer. So a woman has ovarian cancer, or a person has lung cancer, and they are treated with a, usually with a platinum compound, uh, right off. Uh, and What, what's a platinum? So they're, they're, they're, they're chemotherapeutics that, uh, attack, um, uh, you know, attacks DNA. So, and it's also very toxic because it can't tell the difference between a normal and malignant cell.

• 37:48Speaker 02

  So it's targeting proliferating cells, which are cancer cells. But you also have a lot of proliferating cells that are healthy. And that's why so many chemotherapeutics are horrible, because they're targeting proliferating cells and they can't differentiate it between normal and malignant. And so platinum compounds are ones that target

• 38:09Neil deGrasse Tyson?

  Right, right. Just so, so for example, as we came to understand it, um, your hair grows faster than most other things in your body. So that would be a byproduct of the targeting of proliferating cells.

• 38:24Speaker 02

  Yeah, so your eyebrows, your toenails come off. These are horrible. These side effects are horrible. You know, you, I mean, it's, you lose your eyelashes, you know, your tongue, you know, um, gut. Remember I told you, your gut is turning over two or two, three days rapidly. That's why so many chemotherapeutics really are, have such bad GI effects. So, but going back to Gary's question, uh, about combination therapies and resistance. Well, one, with AOH 1996, you know, if it holds up

• 39:04Speaker 02

  for being very non-toxic and effective for treating cancer, of course, you can now, what you do is you, and not just AOH 1996, this happens all the time. The thinking now is we're not going It makes Big Pharma unhappy because they always want one big drug, you know, that's going to treat everybody. But now that the one big drug, or they call it monotherapy, we're moving away from monotherapy and more going towards what they call cocktails. Okay, is that you will put together a variety of drugs, you know, like treating testis cancer.

• 39:45Neil deGrasse Tyson?

  Chuck knows a lot about cocktails.

• 39:47Speaker 01

  I knew that gag was coming. Yes.

• 39:52Speaker 02

  So my joke is that AOH 1996 will be the olive in everyone's cocktail. So.

• 40:01Speaker 02

  So, um, so two things with AOH 1996. Great hope down the line if it proves to maintain its non-toxicity. Um, I hope that we've already done studies in animals to show that it complements a variety of currently used drugs. And in the presence of our drug, we can actually lower the amount of some of these very toxic drugs very significantly. So the animals can have, you know, they can still show very effective growth inhibition of the tumor, but they're not sick, you know, they're not as, you know, so that's one thing.

• 40:43Speaker 02

  But your thing about resistance, this has come up a lot for me for this drug, for AOH 1996. My lab has worked really hard at trying to make resistant cancer cells to AOH 1996. You know, cancer cells love to do this. I mean, like I was talking about the patient, you know, the lung cancer, ovarian cancer patient, they respond beautifully, but in a year or two, their cancer comes back.

• 41:15Speaker 02

  And they're resistant now to like cisplatin or carboplatin. AOH 1996, we can't make a resistant cell so far. And I'm thinking, why? If I, like, a lot of the therapies that are made against kinase is single enzymes. Remember, they do one function and what the cancer cell do, because it's such a little, you know, it goes, you know, so you're treating, you know, like with a kinase inhibitor and, you know, does a cancer cells will now change the enzyme that that used to target. Okay, that that drug would target. So now it's resistant to the drug.

• 41:56Speaker 02

  Um, and cancer figures a lot of different ways to become resistant to drugs.

• 42:03Chuck Nice?

  This is amazing.

• 42:04Speaker 02

  Yeah, it's cancer is like, it's an amazing.

• 42:06Chuck Nice?

  It's unbelievable. Is, is there such a thing as cell intelligence? I'm trying to figure out because as I hear you talk about this and I'm thinking about viruses and these cells that, that tend to adapt and change and, you know, reconfigure. It's like, what is going on that this can happen? Is that just part of our evolutionary process? What, what is going on?

• 42:29Speaker 02

  It wants to survive.

• 42:30Neil deGrasse Tyson?

  I would take a stab at that. There's billions of them.

• 42:34Speaker 02

  Yes, exactly.

• 42:38Chuck Nice?

  Yes.

• 42:38Neil deGrasse Tyson?

  So, so most will die.

• 42:41Chuck Nice?

  Right.

• 42:42Neil deGrasse Tyson?

  Adapt to the thing. The few that do, bottomed in.

• 42:45Chuck Nice?

  There, there you go. That makes perfect sense. Look at that. Awesome.

• 42:50Speaker 02

  Now, if you think about.

• 42:51Neil deGrasse Tyson?

  So, so Linda, I just spoke up out of turn.

• 42:54Speaker 02

  No, you did great. No, you did great. Get here.

• 42:57Neil deGrasse Tyson?

  There you go.

• 43:00Neil deGrasse Tyson?

  You did good. Chuck, when it's a game of numbers, there's always somebody who's going to slip through the gate.

• 43:07Chuck Nice?

  Yep, look at that.

• 43:08Speaker 02

  And, and remember, and it's constantly changing its genome. It's like locks, you know, it's changing the locks.

• 43:14Chuck Nice?

  Right.

• 43:15Speaker 02

  So with the, with resistance now, what I'm thinking with our drug, it's not a single enzyme, it's a hub. You'd have to change all those gates.

• 43:28Speaker 02

  You know, all those proteins coming in and going out. So I have this, I have the hubba hubba hypothesis. For treating cancer.

• 43:37Neil deGrasse Tyson?

  Love it.

• 43:38Speaker 02

  Hubba hubba.

• 43:40Speaker 02

  So by attacking a hub like PCNA, because it controls, you know, all these, this network. If we could identify other networks like PCNA and start targeting hubba, hubba. You really would be shutting down cancer cells. Of course, you have to find them very cancer specific. But as opposed to the very long time strategy of just targeting a single enzyme. You should, you know, for you guys, okay, as opposed to start targeting a single star, you just do a whole galaxy. You know, you target galaxies, hubba hubba.

• 44:23Neil deGrasse Tyson?

  Amazing. So Linda, just so take us out here. What? In five years, 10 years, what does the world look like?

• 44:32Speaker 02

  In five, 10 years? Because it's just been amazing what the last 10 years. I mean, things have changed so much in the cancer therapy field, just in 10 years. You know, from my training in the last millennium, okay, last century. You know, where we thought, oh, we're going to find one cancer gene, one drug, one drug's going to do it all. You know, we were so naive to now the basic understanding that everyone's tumor is different, but now with using molecular signatures, we're getting every tumor's address.

• 45:13Speaker 02

  We're figuring out where they live, okay, not just locally, but figuring out.

• 45:18Neil deGrasse Tyson?

  I know where you live. There you go. I know where you live, Ted.

• 45:22Speaker 02

  Exactly.

• 45:23Neil deGrasse Tyson?

  I know where you live.

• 45:24Speaker 02

  That's exactly what we're being able to do.

• 45:28Neil deGrasse Tyson?

  Chuck is getting Philadelphia on you right there. Oh, yeah. Backwoods Phil- Philly. Well, you don't have to come see me. I'll come see you.

• 45:35Speaker 02

  Exactly.

• 45:36Neil deGrasse Tyson?

  Okay.

• 45:37Speaker 02

  Exactly. But you know, the thing is, is with figuring out the underlying molecular signature of each tumor, person's tumors, their personalized signature of that tumor. And now coupling it with.

• 45:55Speaker 02

  With this molecular signature, you respond to these subset of therapies. So when a lady comes in with breast cancer, you can say, Mrs. Doe, you have breast cancer 6A. And we know that 6A responds to this cohort of drugs and will effectively treat her. And she may be cured. And if she comes, and if she comes out of remission, we check that signature again. And we say, wow, we use this cohort of drugs. So I see, I see great things.

• 46:37Speaker 01

  It's like walking into a store, buying a suit off the peg, or going to Savile Row where the best tailors in the world are and getting a bespoke.

• 46:44Speaker 02

  Exactly.

• 46:45Speaker 01

  Just for you.

• 46:46Neil deGrasse Tyson?

  There you go. That's fantastic. Bespoke drugs. All right. Linda, you said you're from Queens, New York?

• 46:52Speaker 02

  Yeah, Queens, yes, yes.

• 46:55Neil deGrasse Tyson?

  Cancer never stood a chance. She's from Queens, New York. What high school did you go to?

• 47:02Speaker 02

  Uh, so, yeah, so high school, I went to St. Agnes in College Point, Queens.

• 47:07Neil deGrasse Tyson?

  St. Agnes, okay.

• 47:08Speaker 02

  Yes. And then for school, I'm a graduate of City University of New York, Queens College.

• 47:14Neil deGrasse Tyson?

  Cuny, that's where it happens.

• 47:17Chuck Nice?

  A Chuck, Chuck Louve person.

• 47:19Neil deGrasse Tyson?

  Yeah, yeah, Charles Louvre teachers there. Yeah, we got it. All right. Well, Linda, thank you for being on the show.

• 47:25Speaker 02

  Well, thank you. Thank you for having me.

• 47:27Neil deGrasse Tyson?

  Thanks for sharing your expertise and keep at it.

• 47:30Speaker 02

  Thank you.

• 47:31Neil deGrasse Tyson?

  Stop talking to us. Get back, get back to the lab.

• 47:33Speaker 02

  Absolutely, absolutely. They're in there. Okay, they're in there working. Trust me.

• 47:40Neil deGrasse Tyson?

  All right.

• 47:41Speaker 02

  All right.

• 47:41Neil deGrasse Tyson?

  All right, Gary. Good to have you, Gary.

• 47:43Speaker 01

  Pleasure. So glad we had the chance to tell this story.

• 47:47Neil deGrasse Tyson?

  Yes. All right, Chuck. Good to have you there. Always a pleasure. Neil deGrasse Tyson for another edition of StarTalk. Special edition, as always, as Linda taught us once again. Keep working out.