NTRK Gene Fusion as Novel Target for Cancer Therapy and TRK Inhibitors - Sottotitoli bilingue
So starting with the NTRK gene, and then we'll compare between the two trials and what's available data for comparison.
Finally, testing.
I know the recession for testing, so it's going to be only once live.
in which tumor we should start to practice this thing in the arcade.
So usually for molecular diagnostic the way we start in the whole practicing cancer is to do the agnosis and the microscope
or lots by two or more.
I mean, the histochemistry then came to the market, fish, the agnostic, and finally the molecular diagnostic for DNA RNA.
We have diffusion between genes, gene amplification, mutations, and structural rearrangement.
Now, fusions is documented in many genes and it started a long time ago and around the 1950s
the really the first NTRK gene was detected in the early 80s and it took them a long time
till 2000 actually And after it's 18, 17, that we had two drugs approved in the market.
So if we look at the landscape of kinase fusions in the whole solid tumor,
fusions cannot care and all could be robbed and all these, and also then enter, which is the interest.
I'm sorry, the whole mark it's between any of the cancer, the one in the box and the bridge.
It's what enter one and two.
And if you look at the numbers, you don't look at the colors.
Colors just represent the novelty and which one was old and which one they discovered it later.
But if you look at the numbers,
the higher number means the higher fusion and the higher fusion and the entry 1,
2, and and mostly commutatively higher fusion and most of the.
other genes like oncadira for gliblastoma also the same unlike cancer they are the most and higher fusion that present on the cancer.
This graph present that the frequency of patient that patient with the higher
This article was published in 2015 and it is the standard actually reference for our fusion incidences within different solid humans.
Now, the enteric represents the neutrophin, the receptor tyrosine kinase.
And we remember, the whole tyrosine kinase tree, we only know in a very small part of the tyrosine kinase.
And this is part of the tree.
It's an ethrocein, tropomycin receptor tyrosine kinase.
And it has one, two, and three.
And it's simply, if you look at the normal Intrigian, what happens, it's attached and it's used with another region, it's not even related.
It doesn't matter whether it's this gene.
energy, it could fuse with energy and it could present the entergene fusion.
And this has happened during dimerization when the LBD section of the entergene is lost then simply
the gene is will be susceptible to fuse with any other gene that's available.
Entergene and entergene receptors suppressed in your own So,
it's expected it to maintain the health of the CNS function and usually within the fusion, the entry could confuse with any other gene.
And usually the gene does not mutate it or do amplification.
It's only what happens, it's diffusion for the enteric receptors and enteric gene.
Now, as I mentioned that the first drug approved just couple, the low latinib, and intractinib.
And those are the first generation.
And the second generation is one coming to the market is very soon.
And there is many,
many trials also for other generation coming to the Now,
frequency of trek fusion within the body, it's very rare, and the first they discovered it actually in a very rare tumor.
If you look at the left part,
the cancer enriched with the trek fusion,
more than 90% is the rare tumors, like the MSAC MA's SC, which is the salarabic gland tumor.
and the secretory criscals are an adult, and the diethic secretory briscarcinoma and phantile fibrocycoma and cellular mixed congenital mesoblastic lymphoma.
This is why these drugs are tested in adult and pediatric in a very rare tumor.
in the very early brychnical events and stages and then they found it in a lower preference list than 5%
with other tumor, which is the common ones.
But if you look at the blue one,
which is not bad percentage at all, which is 5 to 25% in thyroid, just and also long.
Even though it seems very small,
these percentage is very critical and treatment of silly teamwork because if you look at just for
example it says I have it I highlighted here fan negative, which is the same.
Once the just is fan negative, you expect transfusion and over-ex suppression and patient may be respond to these drinks.
It's the same with the lung cancer.
We'll talk about it right now,
but just just a member that it's very common in a rare tumor, and it's very uncommon in the other common tumors.
So this is the classical pathway,
the gamma BLC pathway, MAP key pathway, which is the rasraaf, and also the mTOR, which equity, bi-3k, and mTOR.
Actually, it's when it's stimulated, it binds to the BDNF, and then it activates the receptors
and it will be also inhibit death 3 pathway, which is the intracellular cascade, which is further will inhibit the cancer.
So the first one came to the market is the micro cycle light and stability and this is the second one.
And actually we call it second tissue agronistic Because it's not it's although it targets,
but it's work and nonspecific in what issue is not specifically
So we call it low latinib and is the second and intracting is the third tissue agonistic improvement.
And the first one for sure is the microsatellite instability and DNA damage repair.
So the first one came to the market is lower tractinib and the second one enter intractinib.
They both approved an adult solid tumor and pediatric and for patients who express an entergene fusion.
And they are not enrolled for any active therapy, that means their second, third, and fourth line.
So it's either metastatic or surgical issues section is likely to result in severe mortality.
and also this factor result.
So almost like when patients run out of the options,
although again, we say if the patient does not harm or any tumor molecular targets, then they are eligible for it.
with it and I will be clear with these things under testing.
Now, this is will give you an example when to test and what you want will be treated with these two drugs which is coming
and so on.
So, L'Oreal Tractinab is highly selective.
It's inhibit the track, fusion inhibitors, and it's tested in three early stages, a phase is trial, and it's approved from these trials.
In that it was less specific,
though, it's inhibit the track, and there was an So it's highly suggested even from the preclinic affair to be used on the lung cancer and it was tested in three adult trials and one pediatric trial.
Now starting with the clinic and that I would learn a in it, a lot of tractative I'm sorry, and then intractative.
Each one I would present it separately and then I would present a managed slide that
it was presented and as more I found it very useful.
So patients in early phases, adults and A small of patients, total number is 122 patients.
The primary endpoint is based objective response and noise is duration is response and progression piece of other environments.
Now, the threat fusion, it was required for this study.
Those was 100 overall BID continuously, and for the dielectric is 100 milligram per meter square.
So this is the results.
If you look at this.
And the minuses mean the shrinkage in the tumor size.
So look at the shrinkage of the tumor size.
The overall response is around 81%, which is very high.
It's an excellent response on these patients where we hope that there was there,
there is no more response that it can be seen at this stage.
And if you look around the cancer,
thyroid cancer,
colon, melanomas, of tissue, lung tumor, just remember again, some of the, the, the, the,
The cancers are a higher percentage,
but even with lower percentage incidence, if they still, if they are heartening, intrinsic gene fusion, that they will be respond from this graph.
Now, for the outcome and over treatment duration, the median duration of response was not preached.
And it's very easy to tell from the first median time response 1.8 months and the assessment,
most of the patient have a complete response and the red dots are the mean partial response,
I'm sorry, and the red dot are the complete.
But then if you look at the nine,
the median duration of nine at 12,
which is one year full of,
still there is a huge number of patients that they still are active treatment and they're still having response for a longer duration.
And this will also suggest that progression is not soon with this medication.
Now, again, the most common tumors are livery, soft tissue sarcoma, infantine.
And this is the same data.
Adverse events were predominantly grade one, which very interesting.
and no adverse event of great tree and forest, so it is really well-tolerated medication.
The most common adverse effect in more than 20% was fatigue, nausea, dizziness, vomiting, cough, increase in L.T.
constipation in the area.
I to also highlight again that those drugs can
produce CNS side effect because of their neuronal mechanism of action because intergene itself exists on the neuronal tissue.
And there was no treatment related With the second drop and trekked in it,
it's almost the same design,
early phases,
primary endpoint with the overall response and duration, and the secondary is the progression of pre-survival doses 600 every day for 28 days.
So it's a once daily regimen.
Now, this is the adult trail, and there is one trail, but I'm including the adult
trail, 54 patients with an attribution positive, and also, 35 patients, overall, will consider all for safety.
Now, if you look at this trial, because from the mechanism of action and big lycoprotein
engagement of intracutinib, I just want to emphasize that big lycoprotein substrate, it's very common in tyrosine kinase, all the small molecular kinase.
So this is why they have to study the big lycoprotean.
If it's highly, if it's less substrate, so it's mean it could work in the brain metastases and we'll talk about that.
So there was a high percentage of patients with not small cell cancer around 20 years ago.
And if you look at the efficacy and the response, it's all almost similar graph from the lower attractiveness.
It was very effective and the response was around 57, so it's lower.
percentage with 7.4 complete response at 50% partial response.
And those are the distribution of cancers, lung, saliva, gland, breast, thyroid, and cholera.
But the median duration was only 10 months while in Larlacatene was not preached after even one year.
So the side effect was more than 20% fatigue, constipation, dizziness, weight increase, cognitive impairment again because of CNS effects.
vomiting, cough, astralgia, but most commonly both side effect related to cognitive disorder and there was no death is related to the treatment.
The next one is the median duration of response.
Again, if you do a patient in one year, there is still a patient's responding, and most of the patient is still active on treatment.
That means they did not progress Now,
they looked at the patient with CNS metastases, again, as I mentioned, that it was from the mechanism of action of endctanate.
It was proposed that it crosses blood brain barrier.
So the efficacy.
The pink one is with the CNS metastasis as baseline and the blue one knows CNS metastasis as baseline
and all these patient groups were responded to treatment.
They did not include CNS metastasis and lower latinib, it was this 10-5 percent.
of the patient so they didn't analyze this group because again it's it was not proposed that it crosses blood brain barrier such as entropy.
So definitely the great an efficacy was seen and patient with or without the and CNS
metastases and those even group of patient had a complete response while they have a CNS.
I think this is very crucial and important,
especially in lung cancer, as we mentioned, because more around 50% of the non-small cell lung cancer patients develop brain metastases.
Now, if we want to combine the two trials just for summaries, We have here the overall response with lower retructinib, 80%, while intractinib, 57%.
The median duration of response was not 3 each,
and lower retructinib, and it was only 10 months, which is, I think, an excellent number still for the solid tumor.
with a progression-free survivor of 11 months, and reach on the attractive group.
So, and this one for the time duration of response, again, this is the duration, 1.8 months.
And you can see that it's much longer response with lower tractative versus intractative.
Now this is a survival modeling or what we call it in economic survival exterability.
They do,
they take these survival and progression free survival models from the original trials,
and they try to see in a lifetime horizon,
which means not in 10 years, not in 20 years, they see forever when all these patients will die.
Now, if the graft is not overlapped with the original graft, it means that there are
still patients who are alive after a long, long time, which is more than 20 years, which proposes curative care.
Now, if you look at a lot of tractative survival, it was in 10 years, still there's around 40%
and 10 is 40% are alive, which is amazing.
And then at 20 years much, it goes lower, but it does not touch the origin of the armpit.
It means there's still patients alive after a long time.
It's definitely not the same scenario, and there was a sharp decrease in survival care with intracting it.
So it gives us a hand that a lower look, and it was higher in survival than intracting.
And, of course, that's it.
It is classical.
We use it in an an economic and they use it in my YouTube and after a long time full of it matches their
survival and exobulation quickly, a interaction.
If you look at the blood brain barrier a big like a protein work as a
guard which is doesn't allow drugs that goes to the brain.
This is a trial used in a novel vitro tissue model,
and they found that Lorelek Teneb has, if you look here, and the red part is a strong substrate and here a weak substrate.
So Intrictorib has a weaker substrate for a big lack of protein,
that means it causes This is why it's from the virtual trials,
they suggested that in Tryptonav can be active in the CNS with us, this is not likely on lectinav.
The last thing in the testing, the trick phasing can be screened by immune history, chemistry, fish, and next generation.
When should we test?
It depends on the tumor type, although it is active across most of the sodium one.
Patients have curable action options.
If the patient have curable action, we should not test.
If they don't have,
then we have Now,
this is not a standard guideline,
and more it depends on the practice,
and next-generation sequences is the standard of practice in many other places around the world, even at King Poisson.
But the problem is that it's a little bit expensive.
So I'll give you an example, and ability for your cancer.
If the patient is be rough, mutated, is 50%, then you don't have to do all the next-generation Thank do.
If they are not be rotated, then you scream for entry by immunohistrochemistry, which is more cost effective than doing the next generation sequencing.
Now long from the beginning, it's recommended to do it because they have lots of genes involved.
So it's good to do the next to do everything together, each of our rascs also and the entrance.
Just mutation, they have multiple mutations.
If they are positive for these mutation, you don't have to test for entry if they are negative.
Definitely, you don't have to waste money and much generation and you can do it in your history.
I'm sure there is so many.
things.
Just summary that all these the two drugs are generally will tolerated, an inter-fusion oxygen driver, a world verification of
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