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SI digital innovations and learning
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is pleased to bring to you a new series on recent advances in clinical neurosciences research with interviews with leading authors of significant pioneering publications for the future You can contact
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us for other topics you would like us to present
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to you.
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In association also with SI, Surgical Neurology International, and with the Medical News Network,
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SI Digital Recent Advances in Clinical Neurosciences Research is pleased to present this lecture in this interview on targeted precision molecular treatment of genetically unique AVMs.
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It'll be presented with Dr. Kiyom Kanod, who is a professor of nephrology in Paris, France.
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The paper we were referring to is his publication from his laboratory on Satorasib for vascular malformations associated with the K-RAS, G12C mutation
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The references is cited at the bottom of the slide.
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Professor Kanod is a professor of nephrology in the section of translational medicine and targeted therapies at the
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Opital Necre on fonts malads
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in the University Paris-Cite in Paris, France. His major area of work is in Interdisciplinary. molecular biology, his references, and his contact information can be seen at the bottom of the
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slide, as he'll be repeated at the end of the talk so you can take a screenshot of that, his contact information. I'm talking this morning with Professor Keoham, Kannad, who's a
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professor in France, and I'd like him to tell us a little bit about his background. So would you do that? Yes, definitely. So thank you so much, Professor Osman. I mean, it's a pleasure to be
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here. Just to give you a brief background about me because you would understand more how I jumped into this new field, I would say. So in fact, I'm a physician and also a scientist. I have a
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research laboratory at Nickair. I was trained as an adult nephrologist, So, kibnest especialist. And I was working on the AKT M top pathway in the context of kidney disease for years. I did my
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PhD on that. I did my postdoc on this pathway. I wanted to move to Boston for two years to achieve a postdoc working on this AKT M top pathway in the context of kidney disease. In 2016, so more or
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less eight years ago, in fact, my life has totally changed thanks to a patient that came to see me with a kidney disease and a rare disorder And this rare disorder was called clov syndrome. It was
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a patient that was having what we call the mosaic disorder, meaning that he was carrying a somatic mutation of a gene that we call Bixi alpha. And that was associated with a kidney disease. And
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starting from these patients, I was extremely interested in an entry by this patient that was in poor condition. I moved to this new field of vascular malformation and overgrowth syndrome related to
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somatic mutation. And in fact, for this patient, we identified a drug that is called anPityzil that's. We demonstrated to be efficient the most with them that we published in 2018 in addition to a
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series of 19 patients. We published that in Nature. And then we were able to push the owner of the drug, that is called Novartis, to move forward. And this drug was approved for this patient who
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speaks with the alpha related overgrowth spectrum in 2022 in the US. So this is a background where I've started to work on all these overgrowth syndrome and vascular malformation From a patient to
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the first US FDA approval of a drug for that kind of recognition. But in fact, as a physician, I'm seeing patients daily between eight to 10 patients every day, every morning. And I'm seeing
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patients that are having many different types of condition. Overgrowth vascular malformation, it can be low flow vascular malformation, but also high flow vascular malformation. And following the
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publication that we had in nature in 2018, we had a huge amount of patients that came to see us And among them, we had a good number of patients with after-uvenous malformation. And in 2020, in
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fact, four years ago, I was contacted by one patients that was living in Lyon in the East part of France, and this patient was having this very serious after-uvenous malformation on the face. And
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this AVM was associated with a lot of pain, chronic bleeding, cellulitis, because he had some skin use aeration and his patient underwent, I don't know how many surgical procedures, radiology
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care procedures, and also he was treated with rapomycin, which is an mTOR inhibitor that was not a success, and he was in ICU every other week. And in fact, this patient was in extremely
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pro-condition, and thanks to the recent progress in the genetic testing, we decided to do biopsy of this AVM. And what we found was that he was carrying Keras G20C mutation. a very specific, not
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that common, but a mutation that you can find in cancer and also in this patient with AVM. Based on that, what we have decided to do here in the lab is to develop mouse models of these Keras G12C
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AVM. So I won't go into details, but we decided to create two different types of mouse models that recapitulated, in fact, the patient malformation and the poor outcome that some of the patients
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are facing. When we had this mouse model that was giving some models that were giving some variant correction results, we decided to use a drug that was ending a faith-renical trial in non-cancer
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for Keras G12C mutation, and this drug was developed by Amgen, it was called Sotoracib. And we asked to Amgen, but also the French regulatory agency, if we could use this drug, as a rescue
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therapy for this patient, and a very targeted therapy for this patient, as a patient and no other therapeutic opportunity. So, we obtained the clearance from the French regulatory agency because
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we have a specific compassionate use program in France that allows that kind of things to provide drug or patient with disease parent cases. And then we started at 960 milligram per day, which is a
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normal dose that patients are using in lung cancer And following the introduction of the drug, I mean, it's an oral pill, it's very simple. What we observed that in a matter of few weeks and
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months, this patient demonstrated improvement. Improvement in terms of symptoms and signs, meaning that he had less pain, less bleeding, the skin ulceration started to heal, he had no more
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cellulitis, he was discharged from the ICU, no more bleeding. And also we saw some aesthetical changes in this patient if you have a look. on the different pictures that are integrated in the
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manuscript, you will see that the face was modified with the treatment. And then we did several MRI to quantify the evolution of the AVM over time. And what we observed is that progressively, the
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volume of the AVM started to decrease up to 30, something percent after two years on treatment And this was also confirmed with doppler ultrasound, the flow was reduced. So we had these first
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patient's efforts that was responding well to the drug and no particular adverse event. I mean, the drug was perfectly well tolerated. Based on that, we started to seek for other G12C mutation in
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our quart of patients with AVM. And we found another patient that was having a very serious AVM also on the face, affecting the hair and she was deaf because of this AVM. or therapies, and a lot
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of additional treatments. And we decided to give her also Soterazim. And we started Soterazim very quickly also. She demonstrated improvement in terms of symptoms. She could recover from this
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deafness. She had less pain, less bleeding. And then after six months on treatment, she had more than 20 reduction in the volume of the malformation. She did develop a great one adverse event
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over time She had the geria, so we had to reduce a dose of soterazib. But then, even with a lower dose, the drug was still efficient. And I can tell you that we have completed the full-up of this
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patient after two years and six months for this to patient. And we have one year of follow-up in addition of these patients. And they are still doing well, not developing any resistance. So, to
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us, this is very important. And this manuscript and this work
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provides many insight for physician, surgeons, radiology. First of all, I strongly believe that all our patients with bad plumb information and particularly AVM after even small formation, they
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should deserve to have a genetic test, you know, because thanks to this discovery, progress in genetic, we can provide targeted therapies for this patient. The important pieces of the message is
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that you need to have a biopsy of the affected area if you want to make the diagnosis of this mosaic mutation. I mean, if you just do a blood test and a DNA test, you will not find the mutation.
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We are talking about patients that are having what we call mosaic disorders. So a biopsy of the affected area is needed. Or at some point, you can do maybe circulating free DNA. starting to be
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developed in this specific field. It's pretty well known in oncology, but in this field of vascular malformation, it's evolving. Genetic test is mandatory. And I guess that that kind of discovery
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of genetic mutation will allow to do drug requisitioning and will help surgeons and radiologists to take care of this patient. We have many, many patients with AVM. We have a court of more than 500
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patients with AVM, mostly pedasic patients, but we also see adute patient. And most of these AVM are located in the brain. And you know that sometimes surgical procedures or even
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neuroadrogytological intermentional, are extremely difficult. And know what we are trying to do here at Nicara, my place. And we're also discussing that with many other physicians is to have a
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molecular confirmation of a mutation and then see if we can try to propose some new drugs this patient some targeted trapeze. in order to reduce the volume of this AVM and then to do us in the second
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time, the surgery of the radiology care procedures. So my feeling, I would say, and my hope will be that we are going to work all together. I mean, for these patients, geneticists,
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neurologists and also neurologists in order to improve the care and the outcome of these patients
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Well, it's an excellent
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summary. So why don't we, we can go, I'm going to just show our audience the paper. Yeah. We can go into a little more detail. You've covered it very well. And here's the paper, I think you
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can see it on your screen, correct? Yes, exactly, I can see it. And this is for the audience. This is a paper that Dr. Kannout and his associates here a road and I was in the New England
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Journal of Medicine just recently. And this was basically
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a summary, and if we want a one or two sentence summary is, is they found that in a couple of some patients that they looked at who had arteriovenous malformations, and this was basically of the
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face, they had a specific genetic mutation, which they were able to biopsy and prove, and they were able to, there is a drug out there that would treat this genetic mutation, we'll talk about how
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it works in a little bit, and they were able to get improvement in people who basically had failed all kinds of therapy for a long period of time, is that correct? Exactly, this is totally correct.
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Okay, I think what I'll do is, I think the next thing we can do is show this picture on the screen, and this is a picture of two patients that you've had, and this is the first man
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who had a malformation. I can just imagine this man coming to your clinic and he's going and he's hospitalized for a whole variety of things in the ICU multiple times, as you mentioned. And you do
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some imaging and the imaging shows this bulging lesion here on the MR scan. And it must have been a risk to you to buy up sea, an arterial venous malformation. You probably thought about that a
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little bit. Exactly, that's a very important point. But since this patient was in very poor condition, the surgeons were extremely good. And these were plastic surgeons, would did the biopsy of
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this AVM into the mouse. And they were able to find some, to collect some tissue from this
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part. And in addition, in parallel, we found that he was carrying the mutation also in some circulating free DNA. So we could confirm that he was having this mutation, Keras G12c. Well, that's
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good. So here are the pictures, and this is at six months and 24 months, and you see the progression at baseline from a lesion area. I hope people can see this. A baseline, a lesion is, it's
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even breaking down the skin barrier on the face, and the lesion is progressively becoming smaller. This is after 24 months of treatment. You can see from a different view here how improved that is.
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And then looking at the larger pictures you have, you can see, and these are the eyes here, you can see the size of this lesion has decreased. So volumetrically, you showed that it's diminished,
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you can see it obviously clinically. And so you must have been thrilled to see that and obviously. from what you said, he went home, he was in the hospital, and so forth. So, I mean, that's a,
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you and your associates must have been very thrilled at that result.
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Exactly, I mean, this was really satisfying and also intriguing to see the improvement and the good outcome of this patient on treatment. I mean, we were not expecting to see the degree of free
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recovery with a drug, but that's a very awful for patients Now, you're still seeing this patient, I'm sure. Has there been further progression or improvement or is it, you think, you know,
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there is? Yes, and so he's still on treatment.
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He's still having progress, but it's going slower compared to the very beginning. So I believe that such as for unpleasive that we identified two years ago for patients with PIXF3C alpha disorders,
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That at some point, maybe. we will reach a certain plateau of efficacy. The patient is not progressing anymore. We have reduced the volume of the malformation, but maybe we are going to reach a
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plateau that will deserve to be improved with surgery. And this will be maybe the next step for this patient. And we are, you know, sinking to combine with some new technique
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of cardiovascular procedures. Interesting. It did, I'm gonna get the picture back here so people can see this I'm sure that they considered embolizing the lesion, but it was, that's probably not
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easy, but some of the considering surgery of this would that further diminish the size of it?
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It's a major undertaking surgically. You're considering that? We are thinking about it, but you know, patients that are trained to work with patients with a physician, they're not trained to work
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with patients with AV and so on, always reluctance to go and to do surgery because they are always telling me, you know, it's bleeding a lot. You may have a lot of complication. And when we have
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a drug that seems to improve the patients, I mean, we prefer to keep this patient on the drug and to move to surgery at the last time. I mean, the surgery will be the last possibility and maybe
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some degree of aesthetically improvement in the near future, but not now Now, this is the, so that it will come to more, the more your patients in a minute. This is a second lady that you saw who
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had a very rapid response from what you just told us to the same drug. And well, here is the paper. The drug is Sodor Sodorisib. Sodorisib, did I pronounce that correctly? Yes, exact. And it's
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paid to the people, it's for vascular malformations, So, it's all just sharing.
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with this crass G12 C mutation. We'll talk about that in a minute. Well, let's talk about this other woman here have here. And this is a lady who had the malformation. It's not as extensive as a
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man, but it's here, you can see it, you outlined it here in the imaging here at six months and you can see how it's diminished in size. It's obviously almost in the mastoid here So that affected
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her hearing and you said her hearing improved. And so she had neurologic improvement plus you don't see the physical defects, but the face may look a little bit less swollenness. So how did she do,
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and is she still improving? Yeah, she's doing very well and she's still progressing. I mean, the treatment is still working well. The malformation is reducing and she's hearing more or less
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normally right now. So that's very, very interesting and very awful for patients. Now, you mentioned something also that wasn't in the paper and that is, and I can see this happening because
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you've developed something people learn about it, they'll learn about it through this video. And so you're getting referred patients with AVMs and it's common in children, AVMs, and they're in the
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brain. And now you've got a more complicated problem and that's by seeing an AVM in the brain to make sure it's a crass mutation. How are you gonna get around that problem? Now, that's a very
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important point. What we know is that most of the brain AVM when they are sporadic, they are due to crass mutation, you're correct. But it's very important to determine exactly what type of
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mutation these patients are carrying because you have different type of drugs that you may be able to, why not use in these patients. And biopsy is a very challenging situation, of course, because
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of the risk of bleeding in the brain. And so what we are trying to do right now, and many groups are doing the same things in vascular animal centers and in the US particularly, trying to collect
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some circulating free DNA, meaning that the DNA from this malformation is released from the endothelial cells. And you can capture this DNA in the blood. And then you can sequence the DNA and with
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a bit of chance, you may find the mutation. This is what we call the
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liquid biopsies. It's another term. And liquid biopsies is commonly used in oncology. The
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oncologists, they're monitoring the growth, the response to treatment. And eventually, the recurrence of disease you're doing these liquid biopsies. So it's very convenient because just with a
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blood test, should be able at some point to determine the type of mutation that is patient occurring. But just to give you an idea, we are using that kind of test since one year, no, and the
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percentage of success to identify a mutation is around 55. So 50, 50, 50, let's say, you have one chance over two to find the mutation. If you don't find the mutation, it does not mean that the
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mutation is not present It just does mean that you haven't found it. I was gonna ask you that because I'm sure in your hospital, I want you to tell the audience about your hospital as an interesting
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history, but you're operating on pediatric patients and these are people who have the AVMs. And I'm sure they could probably get, from even some surgery they're doing today or tomorrow, you can
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get some of the tissue that comes out, You can check it for crass mutation. And then I might give you an idea of what percentage of patients from the total sample have the mutation and what don't.
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And you've already said it looks like you're capturing about half of them, which is I think a pretty large number to begin with with your liquid biopsy. Exactly. And I can tell you also in addition
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that the percentage of patients carrying the Keras G12C
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mutation is extremely low. It's below 5. So that kind of drug soterazib and rosars, because there are rosars drugs that can target Keras G12C specifically. It's only for the minority of patients.
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So it means that we still have a huge amount of work to do if we want to provide new drugs for the other patients. Okay, excellent. I think it'd be worthwhile here to see if we can just go into a
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little bit of the biochemistry of the lesion.
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I picked this picture out. And from the paper, I hope I did the right thing here. But basically, what you have is a genetic change, which is very unique, and that genetic locus then makes a
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protein in the cytoplasm, which is a crass protein, right? And the crass protein influenced by perhaps some outside molecular forces can then activate the system. And then this then comes back to
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signal the nucleus to make the shell grow. Did I summarize it correctly, or can you correct me? Yeah, I think that no, you're still correct. In fact, what the audience needs to understand is
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that the crass protein, they are key proteins in the cell to control the growth and the proliferation of the cell. In oncology, In cancer, they are extremely frequently affected, meaning that
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they have what we call the gain of function mutation, like in the patient that we had. It's a gain of function of activity, meaning that the CRAS protein is permanently activated and activating
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some downstream targets, downstream effectors that are going into the nucleus and that will tell to the cell, you need to proliferate and to grow. And this is exactly what our patients have with
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this AVM They have a single mutation that drives this growth, abnormal growth and abnormal proliferation. What is interesting in our case is that on the contrary to patients with cancer, how
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patients have only one mutation, a single CRAS mutation. And these patients do not have cancer. But if you gain additional mutation, in addition to CRAS, if you have PXF, P53, whatever, Then
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you may develop a concert. So, it is extremely interesting because our patients have a single mutation, they are not developing cancer. If you provide an inhibitor that is specific of this
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mutation, Keras G12c, meaning that it is not affecting the one type Keras, that's why it's well totally routine. It's only affecting the cells that are carrying the mutations. If you block this
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Keras, you may tell to the cell, please stop to proliferate, stop to grow. And then these patients, up to three years of follow-up right now, but more than eight years for the patient with an
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abusive, they are not developing resistance because they do not have additional mutation, such as no quality. And I understand the crass mutation has been around for some, some, I may have
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pronounced it, you said Keras, but the mutation has been around for some time, but the reason people I haven't been able to do anything about it. It's 'cause the spectroscopy or the 3D
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configuration of the protein didn't allow other molecules to come in and stop it. Exactly.
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So what you've got here is a protein that happens to be involved with GTP and GDP, which are energy sources. And if it gets, this is kind of like some people have described an MD Anderson as an
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onoff switch. If the protein is in the off mode, then nothing's happens. The patient won't get the malformation. But if it's in the on mode where it's combined with the GTP, then that stimulates
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all these signaling pathways and downstream pathways that are so growth and so forth and so on. Is that a correct interpretation? Exactly. This is a correct interpretation Soto Azib is
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blocking the Keras. in the inactive mode. So this drug that we're talking about, which is so torosim, it actually binds at the site here so that the Kras molecule, the Kras molecule cannot go
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from
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the inactive stage to the active stage. Did I say that right? Exactly, this is totally correct. And this molecule is only active on this specific variant,
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Kras G12c, and again, you have additional variant, G12d, G13, et cetera, et cetera. That do not respond to Soterazib. Soterazib is very specific for Kras G12c. So it's a very specific
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mutation. And from what I'm reading is, it's involved in non-spal cell lung cancer, it's involved in colon cancer, and in pancreatic cancer. So you're into something here, major implications,
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not only in AVMs, but in other growth, growth terms, is that correct? Yeah,
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in fact, we are, you know, taking messages coming from oncology to do this drug repositioning. I mean, we are learning a lot from oncology, and we are trying to apply what the oncology start
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doing in the field of vascular malformation. And again, we are in what I would say an easy situation because we have patients that do not have cancer. They have a single isolated mutation, no
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single else. So if you block the mutation, whatever the type of mutation they are carrying, the cells are then blocked and do not prefer it anymore. Well, if I'm either the patient who is the man
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or the woman you showed, I had that history, I'll take a 1 chance or even a small single digit chance of having some kind of a positive effect. So I think we understand a little bit how the
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biochemistry of the deletion has, and we've seen the patients, and I wanted to ask you one other thing. You're looking now, you're getting patients who are referred with AVMs, and I can imagine
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in children, some of them are not actually surgically very accessible, so they're inaccessible. They're deep lesions, I'm guessing. And
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we wanna see if they have this specific mutation that they can respond to the drugs, Satora said. Have you had any patients who are pediatric patients like
30:03
that who you've picked up the malformation and you've treated? So this is exactly what we are doing right now. We are sequencing a good number of samples coming from different patients and trying to
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figure out how many of them are carries
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this G12C mutation. But again, it's not a very common mutation, So that's why we need to continue to work to identify other drugs for other patients. But yes, we have observed at least one
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additional patient with an AVM in the brain, carrying this G12C. And now we're discussing with surgeons and radiologists to see if it is a good indication for the drug or not. That's good, that's
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excellent. So
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now as you look at the field and you look at AVMs, and I know you've had an interest in vascular lesions, are
30:51
we going to develop different kinds of drugs that have different target molecules? What do you see in the future being? Yes, exactly. There are, in fact, there are many, many pharma companies
31:02
that are working on that. Because again, Keras is extremely commonly mutated in oncology, pancreatic cancer, lung cancer, colon cancer, as you mentioned. And all these mutations are different
31:16
among the patients. So you have different type of approaches. Companies are developing some what we call various specific inhibitors, such as Sotorazib from Amgen. It's a G12C inhibitor. You have
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some companies that are trying to develop a specific G12D inhibitors. Some are developing a G13V inhibitor. If you use that kind of very specific targeted approach, then you may reduce the rate of
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adverse events, because of course, the other companies that are trying to target all the Keras, whatever is there mutated or not mutated, because it's complex to have very targeted therapy, then
31:59
this drug probably will be associated with some degree of adverse events. So the future to me will be maybe at some point, we are going to move at the very beginning with
32:10
this pump Keras inhibitors, I would say. And in parallel, we will wait for some very, very specific biome specific inhibitors in order to provide the best medicine to the patient. But again, and
32:23
I just would like to be sure that everybody got the message, we are not, I'm not saying that we are going to cure this patient because we are just inhibiting the protein and the mutation is still
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there. We are just saying that we are here to add surgeons and radiologists to do their job to the best in order to reduce the volume of the mRNA formation, the risk of bleeding, and then for
32:49
surgeons and radiologists to work in the best condition Well, tell me a little one of the things we touched on this. I was reading about the history of the hospital you work at. Tell us a little
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bit about that because it started around the time of the French Revolution, so it's almost 300 years ago. Yes, exactly. That's an interesting story because this hospital is pretty old, you're
33:09
correct. And
33:12
here at this place, Linek, was the first to discover the post-cultation with a stethoscope. So we did describe the Osputation here at Nickair. And then you had two different hospitals, one from
33:26
the Pedasic patient, for the Pedasic patient, and one at Duke. And then they were merged 100 of years later. So I know it's called Nickair of Formalad. It's for children and other places. But we
33:36
are mostly in
33:39
Pedasic hospital. And in this hospital, you had the first pediatric transportation ever performed in 1952 It's highly debated with Boston, because
33:52
Joseph Murray was awarded for the Nobel Prize for that. But the first ever was done here at Nickair. Also, you had the first gene therapy here done by Anna Fisher for a patient with a severe
34:06
combined immunodeficiency. And there are plenty of things like that. So this is a very, I would say, famous hospital in France for
34:15
Pedasic population, but also for people
34:20
And I'm extremely proud because here in my research group, we have 20 people. And most of these people are coming from abroad, coming from the US, from Canada, from Asia, I mean, people from
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Japan, from China, from Austria, yeah. So it's extremely diverse. And we are all trying to work together in the same direction to improve the care of the stations. So what you're really showing
34:45
us, and this is a hospital I think it was started by a woman who was with Louis XVI and she wanted a hospital for the poor children and so forth. So you're still a public hospital taking care of all
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people. And so the tradition is going on. And it's called the Opital Neckar, N-E-C-K-E-R, Enfants Maladis.
35:11
And that's in Paris, is that correct? Exactly. Okay. Is there anything that we didn't talk about that I should know or correct me and tell our audience that you'd like to them to know we didn't
35:26
cover? I mean, we have covered everything. I would like to thank you again for this interview and I will be very strongly happy to do one sort of question. I mean, you can find easily my email
35:38
address and maybe you can share it to your audience. If people have some questions, do not hesitate. They do not hesitate. They can contact me Well, what I'll do is I'll make the video, edit the
35:50
video of this and so forth. I'll send that to you. This I'll show you to be up on our website and we hope that that can get people to understand this. I think it's a really a very important advance
36:04
in discovery. So you want to become a neurosurgeon?
36:11
As you stop neurosurgeon Please talk to your surgeon. Now, I think you're all doing what the future is. It's integrated multidisciplinary medicine. It takes a surgeon, it takes a basic scientist,
36:25
it takes a translational scientist, it takes a radiation therapist, all these people have to work together in this problem. And that's what you're doing. Well, I wanna thank you for your time and
36:37
congratulate you and your colleagues for doing it, just a spectacular job. Thank you so much have a very good day. Okay. Thank you very much. Bye. Bye.
36:54
The chief reference associated with this interview is published in the New England Journal of Medicine in 2024. It's entitled Satorasib for
37:06
vascular malformations associated with the K-RAS,
37:12
G12C mutation.
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In addition, there are 25 references in the material presented in this program, and you can find those listed at the end of the author's paper.
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One reference from which graphs are used is this article in signal transduction and targeted therapy from 2021. You can take a screenshot of this and get the references for those graphs
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This is Professor Knud's contact information, which you can see at the bottom of the slide. I take a screenshot of that and you can contact him by email which is listed or by his address by mail.
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We hope you enjoyed this presentation. The material presented in this program is for informational purposes and is not intended for use as diagnosis or treatment of a health-related problem or is a
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There are many ways to learn. A foundation supporting these programs
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SNI Digital is a new video journal of neurosurgery, a 3D journal, which is interactive with discussion. Its web address is SNI Digitalorg,
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Medical news network is also a part of the foundation And it's associated with bringing truthful medical and science news to the world.
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