Let’s Talk About It: Triple-Negative Breast Cancer - Cutting-Edge Research on TNBC

00:00:00:00 - 00:00:24:21
Unknown
Thank you all for joining us. Thank you for joining us tonight. My name is Nancy to Hill. I am the peer facilitator for the triple negative breast cancer. Let's talk about it group. Before we dive in, I just want to go over a tiny bit of housekeeping and let you all know that this we are going to start to expand the scope of the triple negative group and we are going to make it into a breast cancer.

00:00:24:21 - 00:00:48:19
Unknown
Let's talk about a group and invite other members of the breast cancer community to join us. And then we are going to offer some additional triple negative specific programing through share. So stay tuned for more details about that. You'll see some emails come out, but just wanted to personally let everybody know that well, so make it too easy.

00:00:48:21 - 00:01:15:24
Unknown
I'm going to go ahead and mute anybody that's not on mute as well, just so that we we can keep moving. Before we kick off, I'd like to tell you a little bit about share. Share is a national nonprofit that supports, educates and empowers anyone who has been diagnosed with women's cancers and provides outreach to the general public about signs and symptoms because no one should have to face breast, ovarian, uterine, cervical or metastatic breast cancer alone.

00:01:16:03 - 00:01:43:13
Unknown
For more information, please visit shared cancer support dot org. We ask that you all stay muted during this presentation tonight. Dr. Schroeder, When Dr. Schroeder finishes presenting, we'll have a Q&A part of the discussion. Please enter your questions into the chat, into the Zoom chat feature, and I will ask them on your behalf. We are recording this presentation so anybody who speaks will show up on camera.

00:01:43:15 - 00:02:06:13
Unknown
So please enter your questions in the chat. This presentation will be recorded and available on the website and 1 to 2 weeks. So now I'm going to hand it over to our speaker to introduce herself. Dr. Schroeder, thanks so much for joining us tonight. Thanks for having me. Good evening, everyone. I've been asked to tell you a little bit of background about myself before I do dive into the presentation.

00:02:06:13 - 00:02:34:14
Unknown
I've made for you tonight. So I am a professor and department head at the University of Arizona out in Tucson. I've been here since 2002. I've been working in the field of breast cancer since I was in grad school. So in the mid-nineties and my lab here at the University of Arizona really tries to understand what are the drivers of triple negative breast cancer and then also develop therapeutic interventions.

00:02:34:16 - 00:02:53:02
Unknown
And what I'm going to tell you about today is sort of an overview of triple negative breast cancer and then the focus that we have taken to develop some therapeutics. But before I get started, I just wanted to let you know that I'm a Ph.D., not an M.D. So that means that I am a scientist, not a clinician.

00:02:53:04 - 00:03:29:01
Unknown
I work with clinicians a lot. I hope I have great friends at the University of Arizona Cancer Center, and I've worked in a cancer center since I was in graduate school. So so I just want to make sure everybody understands that I'm not here under the auspices of being an MD who actually treats patients. Okay. So I'm going to go ahead and pull up my slides so we can get started all already.

00:03:29:03 - 00:03:55:03
Unknown
We get there. Okay. All right. So I'm starting off with a picture here in the background of normal versus metastatic breast cancer cells. So you can see the point of view from which from which I'm looking at this. So I'm going to tell you a little bit about different cancer therapeutics, which ones have worked, which ones haven't worked, and in the direction that we're taking.

00:03:55:03 - 00:04:26:10
Unknown
And a lot of what I do in my lab is trying to really understand the difference between the normal cells, which we can see here on the right and I'll also I'll talk a little bit about what you're actually seeing in the metastatic breast cancer cells here on the left, because my goal isn't just to understand metastatic breast cancer, but I really want and I believe it's possible to develop a targeted therapy that only hits the cancer and doesn't hit the normal cell to try and avoid all the terrible toxicities that we know are associated with therapeutics.

00:04:26:10 - 00:04:53:10
Unknown
So that is that is the goal of my research to to understand it and to find a way to target it. And to avoid targeting normal cells. While we're doing that. So a little bit of an overview of the cell types that we're looking at just so we're all on the same page. What you're seeing on A and in the slide is a cartoon on the left of the cells of the breast, which are actually pretty unique for most of the other cells in the body.

00:04:53:12 - 00:05:14:22
Unknown
So the cells of the breast form two layers, and both of these layers can actually become transformed and turn into metastatic cancer. So in the cartoon, you can see a cross section of a duct and you can see little pink cells around the edge and you can see some blue cells in the middle. And then this in this in the very center called the Lumen.

00:05:14:22 - 00:05:43:21
Unknown
So if we were to imagine this is a lactating breast, so it's producing milk, these blue cells would be producing milk, and the pink cells would be sort of the muscle cells that push the milk into that center luminance to feed the child. So this is the general structure of the breast. And when we think about breast cancer, we actually know that these two different types of cells seem to be driving the different subtypes of breast cancer that we know about.

00:05:43:23 - 00:06:03:11
Unknown
And this is the cartoon form which you can see here in blue and green is what they actually look like. So these are some breast cells. This is just the luminal cells that we can grow in the lab to try and study how they grow and how they're different from from the breast cancer cells. And so you'll see this picture a couple of times.

00:06:03:11 - 00:06:21:19
Unknown
So I just want to outline what you're looking at. So the blue cells, the blue dots in the center, these are the nuclei of the cells. So this is the the place where the genes are that are being transcribed and cause the cells to behave in the way that it's supposed to. And then the green outlying it is the cell membrane.

00:06:21:19 - 00:06:42:18
Unknown
So the outside of the cell that's communicating with the rest of the world. And in the normal epithelium, this is a normal cells that we were just talking about. You can see how they're just really lined up really nicely and organized. They're all touching each other in a very organized way. And they all are sort of facing this central lumen that I described earlier.

00:06:42:20 - 00:07:16:11
Unknown
This is really indicative of normal cells in that they not only have their genes are not mutated, they're not mis regulated, but but they actually look structurally very organized and under control. And this is one of the things that we know is lost as we get to we go through transformation and cancer and metastasis. And one of the things that we look at in the lab as a marker for changes that are happening, because we know that as we change the genes themselves, this structure will change as well.

00:07:16:13 - 00:07:50:23
Unknown
So those two different cell types that I just described to you respond to hormones that everyone on this call is familiar with hearing about estrogen and progesterone, and they mostly regulate those inside cells as luminal cells. And when we think about subtypes of breast cancer, we know that these guys are regulating those those hormone positive breast cancers. Alternatively, those cells on the bottom and those pink cells in the cartoon, they don't tend to express these and instead they tend to respond to different things.

00:07:50:23 - 00:08:16:11
Unknown
And we these these other proteins are called a herd family of proteins. And a lot of you will will be familiar with her too, because that's a subtype of breast cancer that a lot of people are familiar with. And I'll talk a little bit more about those. But the her family tend to drive very aggressive metastatic cancer. And I'm one of those family members is driving triple negative breast cancer.

00:08:16:17 - 00:08:42:18
Unknown
So we'll get back to those in a second. But just to sort of orient you to who's being who's being expressed where and what they're doing. So so these her family of proteins are expressed in these cells, but what are they actually doing? What they're actually doing is they have an important normal job to do. So in normal cells as well as in cancer, unfortunately, their job is to sit in the cell membrane.

00:08:42:18 - 00:09:06:06
Unknown
So you can see in this cartoon we have a cell membrane here and we have this structure of it, says her three and her two here. But there's any of the her genes will do this. They poke through the cell membrane, they receive signals from outside of the cell. So all cells are sitting in a whole environment of tissues, sending signals back and forth and deciding whether they should grow or move or stay put.

00:09:06:08 - 00:09:27:19
Unknown
All these things are communications between cells in their environment and these her receptors are one of the key communicators in breast cancer cells. So the way that they do that communication is they receive a signal from outside here it's labeled ligand, but we can think of this as a growth factor or anything that's going to cause the cell to change its behavior.

00:09:27:21 - 00:09:48:21
Unknown
And when they bind that signal outside the cell, they start sending off signals inside the cell. We call this signal transduction, and we're not going to go into the details of what's going on here. Just to point out that this is one of the major facets that have been therapeutically targeted for these proteins in other cancers. And we'll talk about what's going on with breast cancer.

00:09:48:21 - 00:10:09:12
Unknown
But in general, they receive a signal, they activate all of these things and the signal cascade happening inside the cell. And the end result of that is you get things happening inside the nucleus, as shown here in purple, that change the different genes that are being expressed. So changes the different proteins that are being made, changes the decisions that these cells are taking.

00:10:09:12 - 00:10:46:10
Unknown
So the biggest decisions that we think about for cancer is it helps the cells decide whether they're going to grow and divide, whether they're going to migrate and invade and metastasize. All those sorts of decisions can be driven by these processes. So just one more time, the different subtypes of breast cancer that everybody has heard of. So we have ace2 receptor positive cancer, which has lots of different names, but these are the sorts of cancers that people would be taking Tamoxifen or Letrozole or something like that for.

00:10:46:12 - 00:11:16:21
Unknown
Then we have HER2 positive cancer for which we actually have a really great drug which is most commonly known as Herceptin. And then finally we have triple negative and it's called triple negative because it's not expressing the HER2 receptor receptor or the progesterone receptor. That's why it's called triple negative. And unfortunately that means we can't use any of these great therapies that we have for her to positive or luminal cancers because it's not making those proteins.

00:11:16:23 - 00:11:39:08
Unknown
And the hunt has been on for a long time to try and figure out what is driving triple negative because certainly there's something driving it. And one of the key candidates for what's driving triple negative is her one, and her one is the protein that I've been working on in my lab. Well, I've been working on her one since I was a graduate student in the middle of the nineties.

00:11:39:10 - 00:12:11:14
Unknown
Her three is another family member. I'm not going to tell you much about that. It's a little bit different in and we'll just leave it to the side for now. But we're going to focus on her one as the driver of triple negative and what we've been trying to therapeutically target in my lab. So an overview of all these cancer types before we really drive into triple negative breast cancer, just to sort of help everybody put it in context of all the very 80 of information they have in their heads about all these different cancer subtypes.

00:12:11:16 - 00:12:55:02
Unknown
So we tend to think of so we've got luminal aluminum B, we tend to think of these as just a group of cancers as the cancers that express estrogen receptor, and they're by far the most common, but they also tend to be diagnosed in a low grade. They tend to be diagnosed before they metastasize. Now this doesn't mean they can't turn into really scary cancers, but because they tend to be diagnosed early and because we have these really, really effective drugs for them, they the prognosis for them upon diagnosis tends to be a little bit better than it is for the her expressing cancers.

00:12:55:02 - 00:13:24:05
Unknown
Now, both triple negative and her two tend to be diagnosed when they're high grade. They tend to have a poor prognosis because they tend to be diagnosed and already be invaded or metastasized. Now, for her too, we have Herceptin, which is shown here with the the drug company name trastuzumab, but it's Herceptin. And in about half of those cancer patients, it works.

00:13:24:05 - 00:13:47:17
Unknown
It works pretty well. But when we get over here to triple negative, which is about 20% of all breast cancer patients, which is a big number, I teach classes on cancer biology and we talk about all the different cancer types and the prevalence of all the different cancer types. And we know that the most common cancers, at least in the United States, are colon, lung, prostate and breast.

00:13:47:19 - 00:14:23:22
Unknown
Breast is is among women the most common right after lung cancer. And so even though only 20% of that number, it's a big number, it's about it's 6040 to 60000 women being diagnosed. Now, when we talk about responses, we actually know that of all these cancer subtypes, triple negative responds the best to chemotherapy initially. And this is actually because it's this high grade cancer.

00:14:23:22 - 00:14:51:04
Unknown
So chemotherapy works by killing any cell that's dividing rapidly. And so this is why we have all the toxicities associated with chemotherapy, GI problems, anemia problems, hair loss problems, because these are cells in your body that are also dividing rapidly. And chemotherapy is not specific for cancer. It's just specific for cells that are dividing rapidly. And so this is why triple negative tends to respond well to chemo right up, right off the bat.

00:14:51:06 - 00:15:19:15
Unknown
The problem is everybody knows is that resistance arises and frequently when you have advanced metastases, they fail to respond, they fail to continue to respond to chemo. So we really, really need to figure out what's going on with these cancers and find some targeted therapeutic that's going to impact them. I think I've already said this, but basically it's just reiterating that were thinking about the her specific cancers.

00:15:19:17 - 00:15:51:21
Unknown
These are these are cancers that tend to be metastatic. They tend to be a lot of times metastatic when they're first diagnosed. And we think about metastases that happen in these patients, they tend to happen in bone, brain, lung, liver. And these are these are, of course, just devastating diseases to have. So again, finding the reason why these her expressing cancers are growing in metastasizing is so important.

00:15:51:23 - 00:16:15:12
Unknown
So I've shown you a lot of cartoons up till now, but I also wanted to show you what the cells actually look like. So what I'm showing you here is an ultra high magnification of a metastatic triple negative breast cancer cell. And this is outlined here. And what it's sitting on is this sort of strange things in the background as it is sitting on some artificial tissue.

00:16:15:12 - 00:16:45:16
Unknown
So it's it's got components of the same tissues that we have in our body that they would normally be grabbing onto. And, you know, one of the things that really strikes you as you look at these images of what these cells actually look like is their ability to reach out and grab the tissue that they're sitting on. Metastatic triple negative breast cancer is is unfortunately really good at moving through tissues, invading through tissues and then moving on to other sites.

00:16:45:18 - 00:17:04:22
Unknown
So as opposed to all the cartoons that we've been seeing up until now, this is what those cells actually look like. And so these are some of the cell types that we work with in the lab when we're trying to figure out what's going on in there. And then we treat them with therapy. And it's, I can tell you, very satisfying when we find a therapy that we can kill these with.

00:17:04:24 - 00:17:26:03
Unknown
Okay. So let's let's take a review of what the current therapies are for these proteins. So so this is another cartoon. It's listed as EGFR and RB two. This is just another name for her one and her two. So the same proteins we've been talking about all along and it's just showing them in a different cartoon. But this again, this is them sitting outside of the cell.

00:17:26:05 - 00:17:56:21
Unknown
This is the cell membrane, this is the inside of the cell. And what we can see is that there's two different types of drugs which are on the market right now and working in in a significant number of cases of non breast cancer, unfortunately. So we have something called an antibody which binds the outside of the receptor. And for her one, this works this antibody works really well in colon cancer had neck cancers.

00:17:57:02 - 00:18:35:23
Unknown
In fact in colon cancer, it's the primary therapy that people receive is this antibody against her one and it works it works really well unfortunately doesn't work in breast cancer. And I'm going to tell you why I think that is. But it doesn't. Then we have a similar sort of situation, an antibody against her two and this is again Herceptin works great in breast cancer in fact, it's the poster child for this type of therapy because it works so well the other way that we have designed therapies to hit these proteins are something called tyrosine kinase inhibitors.

00:18:36:00 - 00:19:00:20
Unknown
The inside of these proteins are enzymes, and those enzymes start that signal transduction, pass process. So being an enzyme means that they can change proteins that they interact with. And so therapeutics have been developed that block the activity of that enzyme. So basically kills it and makes it a dead enzyme. And again, in certain cancers, these therapies work really well.

00:19:00:20 - 00:19:27:16
Unknown
So the two guys against her, one work really well in mutated cases of EGFR. So this would be more much more commonly found in lung cancer. So a lot of lung cancers in people who smoked the type of lung cancer that they develop has a lot of mutations. And this therapy works really well. You may have heard of people taking a pill and there are tumors going away.

00:19:27:18 - 00:19:59:11
Unknown
That's this therapy, unfortunately, has no activity in breast cancer. So and again, similarly for her too, there's something similar. So by now, I think you've all got this this this this part of the story that these proteins are really important. We know they're driving cancer, not just breast cancer, but other types of cancer. We've developed therapies against them, but they don't work in breast cancer, at least the ones to her one don't.

00:19:59:13 - 00:20:24:07
Unknown
And so the question has been for a long time, why? What is going on different in triple negative breast cancer? We know it's making lots of her her one. We know how her one works. We have these therapies that work in other cancers, but it's not working here. So one of the things that I've I've discovered in my lab, but also other people around the country and around the world have have figured out about her.

00:20:24:07 - 00:20:46:12
Unknown
One is that in cancer it behaves very differently. So I told you that it sits on the surface, receives a signal, and then sort of sends off signals on its way. What we know is in cancer is that it's not just sitting on the cell surface, so it's not up here in green like it would be with normal cells.

00:20:46:14 - 00:21:17:06
Unknown
Instead, it gets moved into the nucleus and we call this this is a process by which it binds its protein on the cell surface that it needs to to interact with the outside world. And then it grabs it. And instead of doing what it's supposed to do, it actually heads inside via some some really novel roots, goes right into the nucleus itself and changes all the expression of all the genes itself directly in the nucleus.

00:21:17:08 - 00:21:44:05
Unknown
And when everyone discovered this about 15 to 20 years ago, everyone was shocked because these kind of proteins shouldn't do that. But the reality is people had been studying them in normal cells so long or in other cancer subtypes so long, they never had seen them go into the nucleus. It was only until we started really looking in certain subtypes, specifically triple negative breast cancer that we found them doing this very strange thing.

00:21:44:07 - 00:22:06:01
Unknown
And the interesting thing about them doing this very strange thing is they that could easily explain why they're not responding to those other therapies, because those other therapies require them to be sitting on the cell surface and then to be activating that signal transduction. And they're not doing that. They're going all the way into the nucleus and not activating signal transduction.

00:22:06:03 - 00:22:31:08
Unknown
So the hypothesis in my lab for a long time has been, well, if we can figure out what's taking them into the nucleus, can we develop a drug to block that and keep them from going into the nucleus? And so the therapy I'm going to tell you about today is the result of a couple of decades of trying to understand this process and develop drugs.

00:22:31:08 - 00:22:50:15
Unknown
So I'm going to tell you about one drug that we've developed that's working really well, but it's not the first one that we ever tried to develop. It's actually the third one that we've tried to develop. And the other two, even though they looked really promising at early stages, they fell apart for different reasons. This one is the first one that's made it as fast as it's made.

00:22:50:15 - 00:23:10:04
Unknown
And I'll show you where we're at. Okay. So everything from here on is going to be talking about this nuclear her one. So the one that's not sitting up here on the surface, but instead is down here inside the nucleus directly doing doing things that we don't want it to be doing. So this is a very, very busy slide.

00:23:10:06 - 00:23:44:13
Unknown
But really, it's to point out the differences between these two pathways. So if we look at this dotted line in the middle, everything on the right is what we used to know about what her one does. All that intermediate signal transduction and binding ligand, activating those enzymes, that's all the stuff that we used to know, everything to the left of the dotted line is this this new pathway where it used to be sitting at the surface and it gets traversed all the way into the cell where it's inside the nucleus itself, driving, driving these gene transcription.

00:23:44:15 - 00:24:08:24
Unknown
And we know that it can drive all these things that we associate with cancer progression, allowing the cells to grow, survive, invade. And then I'm going to tell you a little bit how it actually modulates the immune system as well. So so here's another very busy cartoon to that. Again, let's just focus on one little part of it, and that is the part of it going to the nucleus.

00:24:08:24 - 00:24:31:19
Unknown
If you look on the right hand side here it is sitting at the cell surface and all proteins that sit at the cell surface go through a process where it gets in vegetated inside the cell. And that's very normal. What's unique here is they start associating with a group of proteins called sorting nexans and sorting Nexans do what their name might make you think that they do.

00:24:31:19 - 00:24:57:21
Unknown
They sort things out. They sort things and send them to the right place. And these sorting nexans are the proteins that take her one into the nucleus. And what I'm telling you is the result of about ten years and five different graduate students PhD thesis. But that that's what's happening. We have found the carrier that's grabbing EGFR and take it into the nucleus.

00:24:57:23 - 00:25:28:07
Unknown
Now, once we discovered that it was the sorting nexans that were doing the job, that's when we decided to go after them and try and develop a therapy because we reason that if we could block the interaction between her one and these sorting actions and we couldn't have her one in the nucleus, then maybe that would be the thing that we needed to do so that the drug that we developed and I apologize for this is called Sysmex 1.3.

00:25:28:07 - 00:25:46:13
Unknown
It's called that just because whenever we were developing drugs in the lab, we have lots of iterations and lots of changes and we try and keep all those names in the name as we go forward. But that's what you're going to see. Pop up on all these slides is this is this name is going to call it Snakes 1.3.

00:25:46:13 - 00:26:17:19
Unknown
But whenever I'm talking about that, I'm talking about that drug that prevents her one from going into the nucleus by preventing it from interaction with those sorting axes. Okay. So here's a couple of different pieces of data to show you that this drug works and it works in human cells, works in human triple negative breast cancer cells, doesn't work in normal cells and works in a mouse model of breast cancer.

00:26:17:21 - 00:26:40:00
Unknown
So if we look at these graphs up on top, these are these are a data in which we take human cells, we grow them in the lab, we treat them with the drug and then we find out if they've survived or not. Okay. So we go across the top here, all of the cells that have gone across the top, these are all surviving cells.

00:26:40:02 - 00:27:00:06
Unknown
Okay? And as they drop down to the bottom, this is these are cells that are dying. And one of the things that we do in all of our studies is we compare our drug, the snakes 1.3 to the established drugs that people have already made against her one. So in this example, we're comparing it against a drug called Tipitina.

00:27:00:08 - 00:27:29:01
Unknown
And what's Tipitina is, is one of those drugs that blocks the enzyme activity of her one. This is a drug that works really well, and those mutated lung cancer samples that I was telling you about. We also know that it has toxicity, so it's a good way for us to compare how are we doing against the standard of care for trying to target this drug, to target this protein, and then how we do it for possible off target effects, Meaning are we going to hurt normal cells as well?

00:27:29:03 - 00:28:11:19
Unknown
And this graph on the left is triple negative breast cancer cells. And we can see that when we treat with snakes 1.3, we get great killing of these cells, rapidly killing them and they don't come back. This is compared to that enzyme spitting that people use for lung cancer, which also works but doesn't work quite as well. And then if we come over here to normal breast epithelial cells, so these are cells that are not cancer, we found something really exciting and it and, you know, I'm I am super excited that this drug works against breast cancer, but I'm even more excited that it doesn't work against normal cells.

00:28:11:19 - 00:28:37:03
Unknown
And that's what this graph shows. So this graph shows that if we have these normal cells, we treat them with that enzymatic TKI, the one that works against lung cancer, it kills them, kills them even better than it killed the cancer cells. This is one of the reasons we're seeing toxicity with these sorts of drugs, because they're not specific to something happening in the cancer, because these proteins are expressed on normal cells as well.

00:28:37:05 - 00:29:01:02
Unknown
But when we treated it with Snooks 1.3, it didn't do anything, which was really an exciting, exciting discovery. And when we really think about the mechanism and how this working, this is working, we would expect it not to do anything because in normal cells, EGFR or her one sits at the cell surface and hits off that signal transduction cascade.

00:29:01:08 - 00:29:24:15
Unknown
But it doesn't go to the nucleus. It's only in the breast cancer cells that we've seen that it goes to the nucleus. So that actually makes sense then that it's not impacting normal cells because normal cells aren't doing anything. So next, 1.3 is going in there and it doesn't have anything to target. So it's not hitting anything, whereas spitting in is completely destroying the normal cells.

00:29:24:17 - 00:29:48:06
Unknown
So this was super exciting to us. We repeated in a lot of other cell lines, but we really wanted to get it into an animal model that it can. And so the data from the animal model shown here on the bottom and the reason we need to do this in an animal model is that we frequently, I think as a public, we think of cancer as that just there's the tumor, there's the cancer cells, and they're behaving all by themselves.

00:29:48:08 - 00:30:10:11
Unknown
But the reality is there's no cell in the body that behaves all by itself. All cells in the body communicate with their environment. And that's the same for cancer as well. Cancer cells also have to communicate with their environment. And so we need to make sure that the therapies we develop will be functional when a cell is in the very complicated environment of the tissue.

00:30:10:13 - 00:30:32:18
Unknown
So it's not just the local environment, but it's all the hormones that are produced in an animal. It's the the blood vessels, the immune system. All these things impact how tumors grow and how they respond to therapies. And so it's really important to test these in an animal model that has all those different things impacting what's going on with the tumor.

00:30:32:20 - 00:30:55:18
Unknown
So the animal model that we chose is an animal model of breast cancer that's driven by her one. And you can see here on the left, this is the amount that the tumor has grown. And this is each individual tumors. Over the course of a study, we just sort of lined them up all to all here together. And this is a control animal, so they're not being treated with sex.

00:30:55:20 - 00:31:18:20
Unknown
Whereas when we treated them with this next 1.3, we had two tumors grow, but they the rest of them shrunk. They shrunk down to the point where we couldn't find half of them. They were just gone. And this was just so exciting to us that we were we're not just causing status of the tumors, but we're actually causing regression of the tumors.

00:31:18:20 - 00:31:49:06
Unknown
So this is fantastic. Letting us know that that this pathway not only is important, but that we can develop a therapy to induce regression. And and I almost forgot to point out. So this study and the development of this drug was the work of a graduate student, Ben out. Well, who's still in the lab right now working as a postdoc, wanted to of so something that we're of course extremely interested in is the toxicity.

00:31:49:06 - 00:32:10:16
Unknown
So I showed you some experiments where we found out that our drug wasn't doing anything to normal breast cancer cells, but that was just are not normal breast cancer cells are normal breast cells, but that was just one single cell taken outside of the animal. So we wanted to go back into the animal and see if any of the tissues were being impacted.

00:32:10:18 - 00:32:38:10
Unknown
And so we treated mice three times a week for a month and then took their tissues and looked for any sort of evidence of toxicity. We have veterinarians on staff here at University of Arizona who did that work for us. They didn't find anything. No evidence of toxicity at all. So based on all that work that we are, we found this this natural way to target it.

00:32:38:10 - 00:32:59:11
Unknown
And we developed this drug looks like it's nontoxic and it works looks like it works really great in our mouse model. I'm working with a clinician here at the cancer center to try and complete any other requirements the FDA has so that we can apply for a clinical trial to try and get this in people and hopefully, hopefully make a difference.

00:32:59:13 - 00:33:33:10
Unknown
Okay, So this is just a summary summary model showing all the things that I just told you about. But when we think about what's going on, this activity with the natural killer cells is really exciting because we know from a lot of other types of therapies that people are working on that if you can activate the immune system against cancer, it really does an outstanding job of going against and not just killing the cancer in the breast, but the metastatic disease and in fact natural killer cells.

00:33:33:12 - 00:33:51:03
Unknown
That's sort of their claim to fame, is that they're really good at killing metastatic cancer. So so that was that's one more reason why we're we're just super excited that this has a has a strong potential. And I can't wait to see what's going to do when we get inside people. Okay. So that is all that I had to tell you about.

00:33:51:03 - 00:34:14:14
Unknown
I wanted to make sure that I mentioned Ben and Angelica, which I did. And these are all the other students in the lab working on this, working on this process. So I'm going to stop now and take questions. Thank you so much. I mean, I didn't expect to have this reaction, but I found myself, like tearing up a little bit, watching the video of the of the cancer cells dying.

00:34:14:14 - 00:34:34:00
Unknown
And that's incredible. And I think I can speak for all of us. I say, thank you so much for doing that work. Well, let me just tell you, we tear up, too, which is great. And so the results, we get pretty excited. Yeah, it gives us a lot of hope. It does. And so we've had a couple of questions.

00:34:34:02 - 00:35:02:01
Unknown
So one is you mentioned her, one being on the surface of the cell and also being in the nucleus is that I wasn't clear. Is it always on the surface and in the nucleus, or does it only go to the nucleus when it becomes metastatic? I wasn't quite sure on that particular one. So it's always on the cell, it's always on the cell surface and it's always on the cell surface.

00:35:02:01 - 00:35:22:07
Unknown
In normal cells. But almost every cell in your body has her one, which is one of the reasons why there's toxicity associated with that. It works at a very low level most of the time. But then in in triple negative breast cancer, that's when we're seeing in on the surface and in the nucleus. And it's in there in the metastatic cells and in the non metastatic cells.

00:35:22:09 - 00:35:48:10
Unknown
Got it. Okay. We actually we actually know the reason, but it's sort of wonky to get into it so I can get into the view right now. Fair enough. Now, so you mentioned cancer invading and cancer metastasized. And can you clarify the difference between those two terms? So most of you probably know about stage one, two and three and four cancer, right?

00:35:48:12 - 00:36:15:13
Unknown
And so for any cancer to be called cancer, it has to had local invasion. So it can't still be sitting where it's supposed to be. And so this is why the first type of cancer that's diagnosis, stage one, it's it's invaded, but it's still just right there at the local spot if it hasn't invaded. This is where you have things like that to carcinoma in situ, where some things have happened, but it has invaded also.

00:36:15:13 - 00:36:49:14
Unknown
It's not technically cancer yet. And then the different stages go forward, sort of drawing it away from that first site where the cancer was formed. So stage four will be called a distant metastasis, and that means it's left the first site and now it's gone to bone, brain, lung, that sort of thing. It will speak to that clinical trial process a little bit more and how how you would go about getting getting your drug approved now.

00:36:49:18 - 00:37:21:13
Unknown
So so it's it's very involved. But I try to remind myself that it's very involved for a good reason, because it's there to protect us. Right. So the clinical trial process was developed when, you know, in the fifties, physicians were just throwing things in patients that sounded reasonable and a whole lot of bad things happened, Right? So clinical trial process was developed to try and protect us And so there's a whole lot of stages that you have to go through to get something approved by the FDA.

00:37:21:15 - 00:37:49:11
Unknown
So the two big ones are the first is to evaluate toxicity, which which we've done and that part actually is ready to go. The second part is you have to find a way to be able to detect the drug in a patient after you've given it to them. And so the reason you need to do this is you need to be able to figure out how much drug can I give this patient before it becomes toxic, How much drug can I give this patient?

00:37:49:11 - 00:38:14:16
Unknown
And it's still circulating in their blood system, like, how do we design the trial? How often do we give it and how much do we give it? And to do that, you have to have a method to detect it in blood after you've gotten it out. And that's where we're stuck right now. So we're working with a lot of different scientists who are very talented at these sorts of things, and we're having difficulty reliably detecting it.

00:38:14:16 - 00:38:49:07
Unknown
We can find it, but we can't always find it. And it's quite a head scratcher. We don't know why, but we're working hard to figure it out. And so once we get those two experimental things done, the clinician has to write up a clinical trial that goes in with the application, and then we have to work with the companies who are going to make the drug, who are going to decide, decide, you know, how much drug to put in the bottle, how to make the label so that everybody is absolutely clear on how much of the drug to give a patient at what time that has to be written out, you know, really carefully.

00:38:49:09 - 00:39:10:16
Unknown
And so those are all our processes that have to go through as well. And then we sort of take our whole data packet and give it to the FDA and they look at it and decide if if it's they think it's safe enough to try in a phase one. So phase one clinical trial is just safety in a human being because no matter how safe it is in a mouse, it's not a human being, it's just a a guideline.

00:39:10:18 - 00:39:44:00
Unknown
And so phase one is safety and a human being. And then if we pass that, then we can apply for a phase two, which is where we can start looking at efficacy. Does it actually work on the cancer inside a person about it? So I think we all can look back at our pathology reports and see, you know, our hard to designation or are PR is there any testing for for her one in pathology at this point or is it just assumed that every cell has her one?

00:39:44:00 - 00:40:06:08
Unknown
I'm curious about that. No, there's not. There's not. And so the the pathology that we're doing for, let's say, for example, for her, too, I think that's the best example that actually took a really long time to get to the stage where pathologists are routinely looking for that. And part of that process was there's two different ways that it's evaluated.

00:40:06:08 - 00:40:26:14
Unknown
One is called MHC, where they look for the protein and they say, Is there a whole lot of this protein, the cell membrane? And if it is, then I'll give you a grade 1 to 3. And then the other way they do is they say, is there been genetic alterations to the HER2 gene and that's something called a fish, and they'll tell you whether or not that is.

00:40:26:14 - 00:41:00:20
Unknown
And then they'll put those pieces of data together and they'll tell you you're HER2 positive you're her two negative. So for EGFR, sorry for her one, we have a fish test for it for amplification. But it's, it's much trickier than her two because it doesn't just stay at the surface because it goes inside. It's hard for pathologists to give that a number and then because of the reasons for driving it inside to the nucleus, that changes whether or not the fish is important or not.

00:41:00:23 - 00:41:23:20
Unknown
So it's just it's a it's it's trickier than her and we'll work it out. We'll figure it out eventually. But it's just it's going to take some time to figure out all the details. Yeah. Okay. And you just mentioned grades. Can you speak to stage versus grade a little bit? I don't know that we all were given, you know, grade grade versus stage.

00:41:23:21 - 00:41:54:18
Unknown
It might have been one or the other. Yeah. So not all pathology reports will have both. And I'm actually not sure why that's the case, because they should all have the same information. But regardless, grade is how much it's metastasized, how many lymph nodes are involved, that sort of thing, or side stage grade is the cells themselves, if they are highly replicating.

00:41:54:18 - 00:42:24:07
Unknown
So if they see a lot of evidence of cells replicating, then that will mean it's aggressive and it's not well differentiated and that will give it a higher grade. And there's four stages, three grades, is that right? There's definitely four stages. The grades change a lot depending on the subtype of cancer that you have. I mean, like and even like different cancers, like melanoma has something like 12 grades.

00:42:24:07 - 00:42:48:00
Unknown
It's it's very it's a something that's really unique to the subset of pathologists who have decided to define what the stages and grades are for the cancer. So I can't promise that the grades are only three for TMB. C I don't know that that's true, but it might be true. Okay. Just one of those times would be good for you to have a clinician here and statistic.

00:42:48:02 - 00:43:19:05
Unknown
So you mentioned that that her one can be found in other types of cancer, like colon cancer, and it's more treatable in those types of cancers. What other types of cancers might you see that particular mutation? Probably prostate cancer. So prostate cancer turns out prostate and breast have very similar structures. So that bilayer epithelium that I described at the beginning.

00:43:19:06 - 00:43:48:01
Unknown
They're not exactly the same, but they're the same. They're both driven by hormones and they both express the her receptors. So it's not as much work has been done there, but it's likely that's going to be the case. There's also a form of her, one that drives glioblastoma, where this seems to be happening as well. So one of the drugs that we developed along the way, getting to this one, actually worked pretty well in glioblastoma models.

00:43:48:03 - 00:44:16:05
Unknown
So it's likely that that process works in there as well. How interesting do you think that there's a genetic link then to her one mutation, her one mutations. No one has found any heritable, her one mutations. They seem to all be driven by environmental things like carcinogens, and the her one in breast is not mutated. It's just the normal one.

00:44:16:05 - 00:44:50:07
Unknown
It's just a place and it's overactive. Interesting. Okay. Okay. Is is there any hope or thought that the work that that you're doing would be kind of adapted for the prevention of cancer instead of treatment? Not that it not that I know of. You know, when thinking about the prevention of breast cancer, that's going to be a tough nut to crack because most breast cancer is driven by hormones and we're not going to get rid of our hormones.

00:44:50:07 - 00:45:23:11
Unknown
Hormones are good for us. We like them. And so to separate that from breast cancer, that's that's going to be tough. And I, I don't have any data saying that it's preventative. I also the other thing about I'd hate to start doing any treatments with her one inhibitors just because so many cells and so many types of tissues in your body need these for normal function.

00:45:23:13 - 00:45:56:20
Unknown
I wouldn't this seems it seems safer for it to be a short term thing than a long term thing. Yeah. I was going to ask what what what good does her one do in the body? It does everything. So so. So the original name for this is is called epidermal growth factor receptor. And it was originally discovered then that it it made your the hair and your skin grow, your teeth erupt your eyes open.

00:45:56:22 - 00:46:19:08
Unknown
And when people started really digging into it and they did things like they created animal models that didn't have any, Daniels can't survive. So all of the organ systems in your body need it to function, and it's because it does this very basic function of allowing cells to grow, telling cells when they need to die, telling cells to migrate.

00:46:19:08 - 00:46:43:13
Unknown
And you can imagine that as an organism grows, like as a baby grows and you're forming all these tissues in your body, you need those sort of signals to happen. And her one is one of the major driver of the signals. So we all know that triple negative tends to recur perhaps more than some other type, some other subtypes of breast cancer.

00:46:43:13 - 00:47:10:18
Unknown
How does that and you talk a little bit more about that, how does the her one protein maybe affect recurrence or are there any treatments out there that can help prevent recurrence or anything? And yeah, so so I mean, you guys, you guys know about the chemotherapy that people give when they have it and they'll switch it to a different chemo and a different chemo to try and find one that you're not resistant to.

00:47:10:20 - 00:47:42:07
Unknown
And unfortunately, this is why we still have 40,000 women a year dying from breast cancer because this because this happens and we can't find a way to treat it. So her one plays an important role in metastatic recurrence of estrogen receptor positive disease, actually. So patients who are originally diagnosed with the luminal cancers and are treated successfully and will go for 10 to 20 years and their cancer will recur.

00:47:42:09 - 00:48:08:23
Unknown
Many of those cancers have suddenly turned on her won. And so the idea is, well, let's give them one of these therapies that work in these other cancers so great. And then they don't work at all. But yeah, okay. You talked about natural killer cells in the body. Is there a way to to boost those naturally to to kind of help keep that immune response boosted.

00:48:09:00 - 00:48:32:13
Unknown
There is way to boost them. So there's there's, there's proteins that are released in your body that cause them to grow and cause them to be more active. The problem is, is getting them to recognize the cancer because the cancers can can turn off all the lights. And and even though the NK cells are maximally activated, they'll just cruise right by them.

00:48:32:18 - 00:49:12:13
Unknown
They won't see them. So the trick is to turn those on, which looks like we found a way to do X. So would you put that in the immunotherapy category then if, if they're revealing those cells. Yeah. Yeah. That's what we're doing. So we're, we're, we've got a lot of experiments design that we're doing right now that I'm applying for funding for, to, to get to really figure out exactly how it's doing it and see if we can that in any way that data that's why I had you not record that there's that little bit of data because that's brand new data in and it's it's it's exciting and Angelica's just really working on the

00:49:12:13 - 00:49:41:22
Unknown
early stages of it. Yeah That's awesome. And can you speak to any of the other immunotherapies that are out there in the market for triple negative like KEYTRUDA? Does it work similarly to to, to the drug in your lab? So KEYTRUDA is going to work against a different subtype of of immune cells called T cells to killer cells and they have a different set of side effects that the natural killer cells will have.

00:49:41:22 - 00:50:14:22
Unknown
They but it's a different way to activate them than natural killer cells. Those drugs and a study just came out for triple negative breast cancer that is effective. It's just they tend to only work in about 10 to 20% of the patients. And that's because the way that they work. So the way those those types of immune therapies have to work is when a tumor is growing, these these cells in your body called T cells will recognize the tumor and they'll go sort of charge in and try and start killing it.

00:50:14:24 - 00:50:35:19
Unknown
But then they all get turned off. And the reason they get turned off is because they recognize the tumor is coming from yourself. And T cells are a type of cells that they really care about. Is this something not me or is this me? And I'm not going to kill anything. That's me. And so as the T cells run in there, they recognize that the cancer came from me.

00:50:35:21 - 00:50:59:17
Unknown
And so they stop and they sit there and the drugs, the immunotherapies that are being used right now that have been clinically approved, they basically that stop sign and they shut it off again and reactivate them. And then and one of the one of the side effects are, is that the immune system can start attacking parts of your body as well because you've sort of turned off everybody's stop signs.

00:50:59:19 - 00:51:25:20
Unknown
So it's got some toxicity. But a lot of those toxicities can be taken care of with like steroids by your physician and hospitalization. The other thing is unless unless those T cells see a lot of mutations, they're not really going to attack in the first place. And breast cancer isn't a cancer that tends to have a lot of mutations.

00:51:25:20 - 00:51:49:22
Unknown
It's not driven by exposure to carcinogens or sun or any of those things. It's really driven by hormones which aren't carcinogens, and they don't induce a lot of mutations. So because of that, it's going it's always going to be a smaller number of patients who can respond to those immunotherapies. And this is also one of the reasons why we're super excited by natural killer cells, because they don't they're agnostic to mutations.

00:51:49:22 - 00:52:13:18
Unknown
If they see something that they think should be killed, then they're going to kill it. If do you envision do you envision this drug as a treatment for metastatic triple negative breast cancer or would would it be used as well in an early stage cases and in a perfect world? In a perfect world, it would work for everything.

00:52:13:18 - 00:52:36:11
Unknown
But I don't have the data to support that. That's true. So one of the studies that we are still working on is the metastasis study, and we didn't get that data at the same time that we got the first data just because those animal models are different. We know in our experiments in the lab that it blocks experimental metastasis in the lab, but I haven't yet been able to test it in an animal model.

00:52:36:11 - 00:53:10:08
Unknown
And I don't I know. We just don't know yet. Yeah, got it. Wow. In your kind of in your mind, how far out are you from seeing this used in humans? yeah. I wish I knew. Until we get this experiment to work where we can detect it. When we inject it, we can't. We can't put our application into the FDA.

00:53:10:10 - 00:53:30:22
Unknown
And experiments or truck is tricky things to predict. It could work tomorrow. I mean, I could be the data could be sitting there right now in my lab. I don't think it is, but it could be. And then again, it could be months, a year. I just don't know. And then once we get the packet into the FDA, how long is it going to take them to process it?

00:53:30:24 - 00:53:54:22
Unknown
I don't know. From the physicians that I'm working with at the cancer center, they think it should take about six months before they would get approval. And then the clinical trial has to be approved at the clinical trial sites, and that usually takes four months. So I don't know. I wish I knew. Yeah, hopefully you would get a phone call if that data was sitting in your lab right now.

00:53:54:24 - 00:54:04:21
Unknown
Yeah. You can read in my of text they text me. I'm good at that. They text with. Yeah I would say that.

00:54:04:23 - 00:54:29:15
Unknown
Okay. One final question and and then we're going to have to wrap up. So we've heard about blood tests to detect the effectiveness of chemo, particular types of chemo. Do you can you speak to that a little bit? How how important and effective are those blood tests? Would you recommend seeking those out just to kind of keep everything efficient and effective?

00:54:29:17 - 00:54:48:21
Unknown
Yeah, I don't I actually know I don't know about the data. So you do when you have cancer, tumor cells do circulate in the blood and there's been a lot of work to evaluate, pulling them down and using them as some sort of a way to discern how well you're doing. But I don't know about any of the data that's come out of there.

00:54:48:23 - 00:55:11:22
Unknown
Yeah, got it. Okay. We are right on time. Thank you again so much for not only taking the time to speak with us, but for the incredibly important and meaningful work that that you and your team are doing. We are so grateful and hope that you'll come back and talk to us again. We will want to keep track of your work.

00:55:11:22 - 00:55:28:06
Unknown
So I I'll I'll keep an eye out for sure. And I'm sure everybody else will, too, Right. Awesome. Thank you. It was great being with you guys today. Yeah, you too. Thanks again. Bye bye.