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The Living Library of Uveal Melanoma | The Eye Believe Podcast · The Eye Believe Podcast

0:03
hey everybody
0:03
welcome back to the Eye Believe Podcast
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I'm your host Danet
0:06
and I'm actually joined by a guest
0:08
that we've had before um
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back in the early days of the Eye Believe Podcast
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at least for me as the host
0:13
I think you were interviewed recently by Megan
0:15
our co host and she did like
0:17
a kind of like a What's Up, Doc?
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um on her
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but this is doctor Lauren Dalvin
0:22
and she is a I believe
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at the Mayo Clinic correct
0:25
yeah that's right
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and you're in the Midwest
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but I'm blanking on where
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we're in Minnesota and I'm so happy to be back
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yeah I'm so glad to have you back
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so if you guys remember way
0:36
way back
0:37
any of you guys who listen to some of the original
0:39
you know the OG listeners of the Eye Believe Podcast
0:41
you guys will remember
0:42
that Lauren has been working on a project um
0:46
that she called the Living Library of Uveal
0:48
Melanoma and um
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we just wanted to get an update
0:51
I think it's been a few years
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we wanna see where you're at with this research
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and what new developments do you have to share
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so Lauren
0:57
I'm just gonna kind of take it your direction
1:00
let you have let you have the floor
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so you can tell us all the good stuff
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thank you so much
1:05
we have been doing so many exciting things
1:07
um one of the things that
1:09
I would really love to talk about is
1:11
we have tried to expand our initiative
1:13
and I'm trying to use some of my expertise to grow this
1:16
well beyond the walls of Mayo Clinic ideally
1:20
so I know you know Justin Moser very well
1:22
and so we've been working with Justin Moser and A Cure
1:25
In Sight
1:25
some of you may have seen the call for tissue samples
1:30
and information donation to the Insight Biobank
1:34
so that's been a really exciting thing for us
1:38
to be able to
1:38
use some of our expertise on building models
1:41
so that we can hopefully
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grow this into something that really
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has a big impact across the country
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and is hopefully
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a resource that's available to all uveal
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melanoma researchers
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I think that's amazing it's so cool
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and I love like
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even just in its new launch phases
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we're seeing how the Insight Biobank can be used
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like
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in real time to help real research that's happening
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like now
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not like in 20 years um
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and I think that's one of the things that we
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as patients like
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really want right
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especially when we're kind of those like
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people who understand more of the
2:16
the gravity of our disease
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whether it's because you're metastatic
2:19
or you're higher risk like
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we wanna know that the research that is happening
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is happening in our lifetime
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that you know
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that it has a chance right
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at helping us or at a at a very least
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helping somebody very soon
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like after
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you know our time of being diagnosed
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and I think that's so critical
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oh good
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I really do I think that's super important
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that we're getting things that are actively happening
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right now and that's one of the great things
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about having these organoid models
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and being able to generate them from patients
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sort of in real time within weeks
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so that when we have valid drugs that we can test
2:55
we're going to be able to feed back that information
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quickly
2:59
yeah like
3:00
it's super exciting to see like
3:02
science come together um
3:04
what are some of the like
3:05
the models that you've been growing
3:08
I guess let's backtrack
3:09
maybe give a little bit of a summary of like what
3:11
what does that mean like
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these models that you're growing in the lab
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um what was kind of the original
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founding idea behind growing these models and
3:19
you know where are you at with the growth of them
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and have you done any testing
3:27
yeah thanks for that
3:28
great question we have first started this
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really
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just out of the idea that our uveal melanoma models
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currently existing in the lab
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that most people use are clearly
3:40
not working well for what we need for our patients
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we have seen over and over and over again
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that we have really exciting
3:48
promising results in the laboratory
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and we make it all the way to a clinical trial
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and that clinical trial unfortunately
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has some disappointing results
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and so one of the papers that we published recently
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we actually did a comparison
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looking at our traditional
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commercially available cell lines
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we looked at our organoid models
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and we looked at our organoid models
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broken down into a two dimensional culture
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as opposed to the three dimensional culture
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and what we found is that the traditional
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commercial cell lines
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that you can buy off the rack for uveal melanoma
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tend to be very sensitive to drugs
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and that may be artificially so
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such that that could explain
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at least
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part of why we're not seeing some of the results
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that we have wanted to see
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in historical clinical trials
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for uveal melanoma
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our models tend to be a little more treatment resistant
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so we looked at several different drug combinations
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that we know looked really good in the lab
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and then ultimately didn't work out for patients
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and we showed that our models
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compared to the off the rack cell lines
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are actually more representative
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of what we saw in those clinical trials
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and then we looked at some newer drugs
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the drug that we chose for our surrogate
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positive control is the Darovasertib drug
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and we saw
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that
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we definitely do have some subtypes of uveal melanoma
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that are more sensitive to that
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that's consistent not only in the off the racks lines
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but also in our models as well
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so this gives us a lot of hope
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that the models we're putting out there
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that we're now sharing with other researchers
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are actually going to be more representative
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of what will happen in the clinical trial phase
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so that when something works in the lab
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hopefully we're actually going to see that pan out
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for our patients in the clinic
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I think that I had no idea that
5:35
that you could purchase you know
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as a researching team as somebody
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you know
5:39
trying to get to a clinical trial with drug development
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that you could like
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purchase uveal melanoma cells that have just kind of been
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like you said potentially artificially grown or like
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you know we've copied it
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but like
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have we really copied it because
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like you said if
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if you're experiencing good results in a trial of the
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of the drug on just cells
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but then you're taking it to people
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and you're not seeing the same result at all
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then like
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there's a big disconnect there
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so I love the idea of using um
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the living library and just using the models
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that you guys have been growing
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to bridge that gap right
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because it's so sucky I'm sure
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for drug developers to just be like
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well it worked
6:14
it worked so well in the cell lines
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why isn't it working for the people
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um and so I
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I mean it sounds like
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ultimately it would be really cool if like
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every clinical trial
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was able to test their drug against your cell lines
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you know against the living library against
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you know tissue from the biobank
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tissue that is like
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from living ocular melanoma patients
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ugh man
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I love the direction that this is going
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it's so cool
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and that's that's exactly the hope
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you know
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the hope is that we sort of skip these false positives
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we don't subject patients to things that ultimately
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aren't gonna work
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and that the models we're using in the lab
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really behave
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and represent what we're seeing in our real patients
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and that they're not something
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that's been in a dish for decades now
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that has mutated
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and no longer behaves like the cancer we see
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yeah well
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and like
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when I think about this from
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from a clinical trial perspective of like okay
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you start with like
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a phase 1 right
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phase one is typically we've gotten past the cell lines
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if and you can correct me if I'm wrong
7:17
but I've been kind of thinking about this
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and ruminating about clinical trials
7:21
for my own purposes um
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but phase one is when
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there might be some kind of drug escalation
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but ultimately it's just
7:28
is the drug safe that's
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that's the goal of that um
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so
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if they're doing the drugs against the cell line first
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and they happen to use it
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you know in um
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a cell line from like
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the living library one that is a
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like more unique to uveal melanoma itself
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not something that is kind of
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grown to be different over time
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um then is it possible to like
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kind of go into say
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a phase 1 trial with more confidence
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that you're going to be able to treat patients
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you just now need to figure out
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what dose is safe for that
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I don't know if that make
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that makes sense oh
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that's a fantastic question
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I think that is exactly the goal
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we're going in hopefully with better hope of efficacy
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that that result we saw in addition
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the lab is going to actually translate to what we see
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in reality in our living patients
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we also have some in between steps that we can do
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that may also support phase 1 clinical trials
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so we have been able to create small
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animal models of uveal melanoma
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that actually use our organoids
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from the living library and so we can create eye tumors
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that we can actually get fundus images and OCT images
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just like we would monitor tumors in human patients
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and we can get little miniature CT scans
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so we can monitor the liver and monitor the lungs
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and so we can actually track tumor progression
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in a living model in the lab
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and that living model beyond what we can see in a dish
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will also allow us to get some safety indicators
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and so we can not only support
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hopefully having more effective therapeutics
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going into clinical trial
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but hopefully
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having some good data that those are also safe
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yeah that would make a huge difference
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I think especially for those
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like phase 1 trials
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that are just trying to get off the ground
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if there was more kind of backing
9:50
their choices and backing
9:52
you know whatever it is
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that they're putting in front of patients says hey
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we've got this drug we've got this combination
9:57
we really think that this is a good idea
9:59
we need you know
10:00
15 clinical trial participants to get this going
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we need you know
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a maximum of 75 like
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the enrollment I feel like
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would be I feel like it would be easier to enroll
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as a patient with metastatic disease myself
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it would be easier to enroll in a clinical trial
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that is in phase 1 because phase one
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to me right now like
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when I think about it
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it feels like we're throwing a noodle at the wall
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or like we're just taking a shot in the dark
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because there's no data around uveal
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but
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if we can come into it with some kind of clinical data
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that says no
10:30
no no
10:30
we do have response in uveal
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here's where we got that response
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and because of this case this case
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this case this case like
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like these you know
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these examples of
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where we were able to put the parallel
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of the organoids
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next to the actual response rate of the patients
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like that just lends itself to so much more confidence
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going into a phase 1 clinical trial
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and I I mean
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I would hope that trials would get to move faster
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because patients wouldn't be so terrified
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of joining a phase 1 trial
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I think that's a fantastic goal
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I think rapidly accelerating
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what we can offer to our patients
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is really a huge impetus for continuing to grow this
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and it's not just all uveal melanoma generically
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I think one of the wonderful things
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about having built this living library
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we now have more than 50 different models
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from different patients
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and so these things have different molecular profiles
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they have different gene expression
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and so we're actually able to represent
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a variety of different
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personalized subtypes of uveal melanoma
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and we can see when we do drug testing
11:34
some of those subtypes
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might be very sensitive to a certain drug
11:38
some of them might be more resistant
11:40
some of them might need a particular drug combination
11:44
and so we actually may be able to predict
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which subset of patients are gonna most benefit
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from being on a particular trial
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so that we could more quickly direct those medicines
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to the right patients yeah
11:56
like so it's not just put the call out to everyone
11:59
it's no no no
12:00
we need patience with this
12:01
this this and this
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like these are the main criteria
12:04
and it just it narrows it down so much
12:06
like I literally
12:06
was reading a clinical trial breakdown yesterday
12:08
and I kid you not it just had this like
12:10
giant list of things
12:12
and in the list of things happened to be one dot
12:15
that said uveal melanoma patient
12:17
like as one of the criteria of eligibility
12:19
and it's like okay
12:20
well that doesn't tell me much
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like what type of uveal
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like what type of uveal patient are we looking for and
12:26
and in the metastatic community
12:28
I'm sure you know
12:29
like we have HLA
12:30
O2O1 and prame
12:32
that there's plenty of trials that have been kind of
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circulating and continuing through
12:36
that are focused on those two expressions
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but not everybody has those expressions
12:40
and so then the rest of us are left sitting here like
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okay but what about us
12:45
um so I think it'll be really neat to see how this can
12:48
how this can evolve
12:49
and just really change the landscape of like
12:52
how we approach clinical trials
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both as patients and how you guys approach
12:56
sending patients to clinical trials
12:58
you know
12:58
based on characteristics that are deeper than just
13:01
you have metastatic uveal melanoma
13:04
you're absolutely spot on with that
13:06
and so it's my hope as this grows
13:09
it's really gonna be a public
13:11
community facing resource
13:12
so that companies or researchers
13:16
who have something that might be interesting to test
13:18
can actually do that
13:19
and not in just one subtype of uveal melanoma
13:23
that might not represent most patients
13:25
but in a panel of subtypes
13:27
so that we're going to know okay
13:28
this works maybe for X Y
13:30
and Z but maybe not for A
13:32
B or C
13:33
but this one's good for A B
13:34
and C and
13:35
and so it's really I think
13:37
the beginnings of what's gonna be a rapid boom
13:40
we've seen the clinical trial boom now
13:42
is happening in uveal melanoma finally
13:45
after decades of of not doing
13:48
really any of these clinical trials
13:50
for patients in this particular disease
13:53
so now I think
13:53
we have the models that are going to support this
13:56
really coming forward at a much more rapid pace
13:59
just as you said
14:01
okay so I have another question
14:03
um I know your living library
14:05
typically has been organoids
14:06
that were taken from the original eye tissue correct
14:10
we started with that and we have actually expanded
14:14
so okay
14:15
so we're taking liver tumors or whatever tumors
14:18
now we are taking metastatic tumors as well
14:21
so we have some liver metastasis in our biobank
14:25
we also even have some lung and bone metastasis
14:28
in our biobank as well
14:30
so this is gonna open really
14:32
a new frontier
14:33
to see our metastasis different in different locations
14:37
and we have some organoids
14:39
that are from the same patients
14:40
from their eye tumor and paired with a liver metastasis
14:44
so we can actually study how these tumors evolve
14:47
and change over time
14:49
because another one of the problems that I see
14:51
that happens a lot of times with uveal melanoma research
14:54
is most of the author
14:56
AXL lines are from primary eye tumors
14:59
and it's great to have something
15:01
it's great that they grow
15:03
and that we can work with them
15:04
but those again
15:06
may not represent metastatic disease
15:09
which is really one of the biggest areas of need
15:12
yeah absolutely
15:13
um okay
15:14
so say somebody had a biopsy like
15:17
you know two days ago um
15:19
and they did six core samples
15:21
is what they told you like
15:22
is that a sample from a metastatic biopsy
15:24
that you can work with like
15:26
is it is it worth it for that patient if they wanted to
15:29
to like
15:29
get that sent to you um
15:31
and if so like
15:32
how does that process work
15:34
so we have a um
15:36
nationwide protocol now so
15:38
we can consent a patient
15:39
from anywhere in the United States
15:41
who wants to send us tissue from a biopsy sample
15:44
and we can generate an organoid for them
15:46
um the best way would be to contact us
15:49
before the biopsy happens
15:51
because the best way to
15:53
give us a great chance
15:54
of growing a really good organoid
15:56
is to actually have the kit
15:58
with the cell preservation media
16:00
shipped and available to that person doing the biopsy
16:03
the day of the biopsy that way
16:06
the tissue that you don't need for a clinical diagnosis
16:08
or clinical tests
16:09
can go directly in that preservation media
16:12
and then those can get overnighted to us on ice
16:14
and we've had really good success generating organoids
16:17
when they're shipped to us overnight
16:38
yeah that makes sense
16:39
so I guess I'm just thinking like
16:42
you know in my particular case
16:44
maybe not gonna work
16:45
unless they happen to preserve it really
16:47
really well the last two days
16:49
um but I could always ask
16:52
you can always ask yeah
16:53
it depends on how things are
16:55
are preserved once things go into formal
16:57
and then we know the cells are not alive
16:59
that doesn't mean that we can't do molecular testing
17:01
and find like
17:03
a twin in the biobank
17:04
that has a very similar profile to a particular tumor
17:08
that could be tested
17:09
yeah I guess that's like
17:10
still worth a shot but knowing about it
17:12
going into a biopsy I think that like
17:14
sometimes the challenge is that
17:16
you know as metastatic patients
17:17
if you have metastatic disease
17:18
show up in a particularly odd location
17:22
like that doesn't really hit the
17:25
the markers like okay liver
17:26
lung bones
17:28
maybe lymph nodes maybe the skin like
17:31
but those are kind of the only five that really
17:33
tend to come up
17:34
and then you have just other random spots
17:36
like literally anywhere
17:38
um and
17:38
and we understand that you know
17:40
from a micrometastatic perspective
17:42
obviously that's how this disease works
17:44
but um
17:45
going into you know
17:47
a biopsy
17:47
and having something show up in a bizarre location
17:51
then kind of layers that situation
17:53
I think at least it did for me
17:54
like with some question of like okay
17:55
but is this primarily uveal melanoma
17:58
or is this something completely different
17:59
is this a cyst is this like
18:01
breast cancer or
18:02
you know just there
18:03
there were like
18:04
more questions just because
18:06
the location was not conventionally heard of
18:09
um so anyway
18:12
sounds like it would be smart
18:15
at least if you you know
18:16
want this level of of contribution to
18:18
to research it would be smart
18:20
if we just make sure that we reach out for that kit
18:23
ahead of time and just have it on hand
18:25
like worst case
18:26
we send it to you and you're like
18:27
hey actually
18:28
this is not you feel melanoma
18:30
never mind but um
18:33
is the kit
18:34
is it something that comes uniquely from your like
18:36
from your clinic
18:37
or is it something that's linked to the inside Biobank
18:39
now currently
18:41
for the organoids we are shipping from our center
18:45
I think the Insight Biobank
18:46
my hope is that we can grow that
18:48
and have a partnership
18:49
where we're able to generate those organoids for them
18:53
Insight is great at storing things
18:56
but an active lab is needed to actually
18:58
initially generate the organoids
19:00
and then expand them so that we can create the stores
19:03
that we need to later share with other researchers
19:06
yeah for sure
19:07
oh my goodness
19:08
so many so many things to think about
19:10
um but this is all really like
19:12
really good stuff really exciting
19:14
and I'm excited to hear
19:15
that you guys are expanding the organoids
19:16
to include the metastatic
19:18
and it'll be really interesting to see um
19:20
any of those patients that you're able to line up
19:22
tissue from the eye the liver
19:24
and any other locations like
19:25
and and see the differences
19:27
um I did have kind of a funky question
19:29
when you say you test the drugs on an organoid
19:34
like what does that look like
19:35
do you have like
19:37
I don't know
19:38
do you have a petri dish full of cells that you can see
19:40
and you just drop drop
19:41
drop the drug on it or like
19:43
what does that look like it is
19:44
it is very much like that
19:46
so we have really um
19:48
specialized petri dishes
19:49
that have lots and lots of wells in them
19:52
so we usually do these in a miniaturized format
19:55
in a 96 well plate
19:57
so it's basically like a rectangle that has 96 teeny
20:01
tiny little petri dishes in it
20:03
and then we can grow up really little
20:04
itty bitty organoids in those
20:06
and so we can do a variety of doses of the drug
20:09
since we have 96 slots
20:11
or we can do some different drugs
20:13
since we have 96 slots and often
20:15
we will do a panel of organoids
20:17
that are different on that 96 well platform
20:20
and usually we are applying the drug
20:23
we're letting the drug work
20:24
usually for three days
20:26
when we're doing things in a dish
20:27
and then we can check viability
20:30
we can check live dead
20:32
and we can look at the cells under the microscope
20:35
and actually see if we still have healthy organoids
20:37
or if they've kind of shriveled and shrunk and died
20:41
yeah for sure
20:42
so like
20:42
looking for that response
20:44
um that's really neat
20:45
and like
20:46
I mean it just feels like in science class a little bit
20:50
like I mean
20:50
obviously way more advanced
20:52
but like
20:52
I remember we like
20:54
did swabs of gross germs around the school
20:56
and then we like
20:57
you know stuck it on a petri dish
20:59
and the goal was to see like
21:00
how germy could we get it
21:01
and some of the germy locations were surprising
21:05
um but like
21:06
seeing the kind of just the
21:08
the layout of how you guys are able to just
21:10
very meticulously test um
21:13
not just one cell line but like
21:14
various organoids and the way that they respond
21:17
I just I think it's
21:18
I really think that it's game changing
21:20
and I hope it continues to be game changing
21:22
for the remainder of the treatments that we have
21:25
you know on the table and
21:27
and hopefully continues
21:28
giving us answers as to why some patients respond
21:30
better to say
21:31
PKC inhibitors versus immunotherapy of a different sort
21:35
um
21:35
and all those answers are obviously still in the works
21:38
but um
21:39
but I'm so grateful Doctor Dalvin
21:40
for you for like
21:42
being part of this and for just conceptualizing this
21:44
and bringing it to life literally
21:46
I think it is one of the coolest ideas in science
21:49
that I've ever heard of thank you so much
21:52
I I'm really excited about it too as
21:54
as you know and I probably expressed before I
21:56
I just feel that changing the game
21:58
and contributing to better treatments and hopefully
22:01
cures for patients with uveal melanoma
22:04
is such a big purpose in my life
22:06
and I I really hope that from early in my career
22:10
to mid career to late career
22:12
everything is gonna be completely different
22:14
about this conversation
22:15
and we're gonna have so much more hope on the horizon
22:19
yeah absolutely
22:20
okay so final little finishing touches
22:22
if someone wants to get a hold of you
22:24
because they know they've got a liver biopsy coming up
22:26
or you know
22:28
whatever type of biopsy in the metastatic world
22:30
and they want to make sure that they can get a sample
22:32
to you what's the best contact information
22:35
and we can also put this in the show notes
22:37
for them to be able to reach out
22:38
yep um
22:39
email is probably the best way
22:41
and then I may connect you with my research team
22:43
so that we have logistical support
22:46
um but that's Dalvin.Lauren@Mayo.edu
22:49
okay awesome
22:50
well Doctor Dalvin
22:51
thank you so much for being here today and chatting
22:53
and giving us an update on your
22:55
living library of ocular melanoma and um
22:58
we look forward to seeing where you go in the future
23:00
thanks thank you so much for having me