Pancreatic Cancer Research

May 10, 2021

Information

May 9, 2021

Yale Cancer Center

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00:00Support for Yale Cancer Answers
00:02comes from AstraZeneca, dedicated
00:05to advancing options and providing
00:07hope for people living with cancer.
00:10More information at astrazeneca-us.com.
00:14Welcome to Yale Cancer Answers with
00:16your host doctor Anees Chagpar.
00:18Yale Cancer Answers features the
00:20latest information on cancer care by
00:23welcoming oncologists and specialists
00:24who are on the forefront of the
00:27battle to fight cancer. This week,
00:29it's a conversation about pancreatic cancer
00:31research with Doctor Luisa Escobar-Hoyos,
00:33Doctor Escobar-Hoyos is an
00:35assistant professor of therapeutic
00:37radiology at the Yale School of
00:39Medicine where Doctor Chagpar is
00:41a professor of surgical oncology.
00:44Luisa maybe we can take a step back
00:47first and just tell us a little bit more
00:51about yourself and what you do.
00:53Sure, I am a cancer scientist.
00:56I basically try to understand
00:58at the molecular cell level,
00:59how do cancer cells work?
01:01I am originally born and raised in Columbia,
01:04South America, but I always had a
01:07passion to come to the US to train
01:10in cancer biology and therapy.
01:12And this was based on an
01:14inspiration because my mom is
01:16also a cancer scientist and she
01:18inspired me from a young
01:21age to become a cancer scientist.
01:23So Fast forward a few years I
01:25came here 10 years ago with this
01:28big dream to make a difference
01:30for cancer and especially for
01:32the patients and their families.
01:34And recently a year ago I started my
01:37own lab here at Yale and in my lab we
01:39have different individuals that
01:42are training in research.
01:45So at this level we have
01:47graduate students and
01:49Master students and pH D students and
01:52we also have postdocs that come to
01:55train after their PhD level before
01:57they can launch their own lab.
02:00So my job as a mentor and as
02:02a leader is to manage all the
02:05research activity and programs that
02:07are being funded by different institutions,
02:10government or private
02:12institutions and it's all with the hope
02:15that we can cure pancreatic cancer
02:18and change the course of this disease.
02:22Tell us more about that.
02:25It sounds like a lofty goal to
02:28find a cure for pancreatic cancer, and
02:32change the course of this disease. But how
02:35exactly are you doing that?
02:37We try to understand this disease
02:40by using as many
02:42biological systems that we can,
02:45so we start by first understanding
02:47the tumors from the patients.
02:50So to do this,
02:51we dive into doing DNA sequencing,
02:54RNA sequencing proteomics
02:56to really understand
02:57the building blocks of these
02:59cells and from those analysis
03:01that we generate from the tumors,
03:04but also with clear understanding
03:06of the clinical need to develop
03:08new therapies to diagnose it early,
03:11that's when we start combining
03:13how can we use the data that we're
03:16receiving from the patients to answer
03:19these questions that the clinical
03:21field is being challenged with.
03:23Then we go and we start engineering
03:26different model systems
03:28where we tightly control the variables.
03:30So for example,
03:31in cells we can manipulate the
03:34expression of genes and proteins,
03:36or in mice we can actually introduce
03:39mutations to the mice in their pancreata
03:41and lead them
03:44to form tumors that
03:46later we can use
03:48all these models combined to test
03:51different hypothesis related to the
03:53basic biology of the cancer cell or
03:55to test novel therapies that
03:58either we generated or a pharmaceutical
04:00company comes to us because they are
04:02interested in testing it in our models.
04:05So I guess what I'm trying to say is
04:07every time you're going to learn such
04:10a complex disease as cancer,
04:12you need to take advantage and
04:14generate as many model systems to
04:16interrogate the hypothesis that is behind it.
04:19So we do this in a team based effort.
04:22In my group we not only have people
04:24that are interested in basic science,
04:26but we also have clinicians or
04:29individuals who are in clinical training.
04:31So we can bring all of these areas
04:33of thought into these questions and
04:36these experimental designs that we do.
04:38We also bring computational scientists.
04:40For example,
04:41there is a lot of data out there
04:43that has been derived from multiple
04:45institutions and across the world of
04:48sequencing from the patient samples.
04:50And sometimes we can build those
04:52databases in house,
04:54but we also take advantage of all of
04:57this data that is being deposited
04:59out there from other scientists too.
05:03So as a community we can actually
05:06develop and better
05:09understand these tumors
05:11and also come up with
05:12better ways to treat them.
05:14And so by sequencing you mean
05:17sequencing the genes of the
05:19tumor itself?
05:20Yes, so what we do is we sequencebthe
05:23whole genome of that tumor cell.
05:26So we're looking at more than
05:2995,000 genes at the same time.
05:31And we are interrogating,
05:34are there mutations on these genes?
05:37How differently is a gene being turned
05:40on or turned off between normal cells and
05:43cancer cells and when we turn them
05:46on do they produce a single protein
05:49or do they produce multiple proteins
05:51from that same template of the DNA?
05:55And so that level of complexity and
05:57imagine all of this,
05:59all these 95,000 genes mutations,
06:01expressions on and off
06:03times the number of cells in a tumor and
06:06all the patients that are
06:08coming for us to analyze.
06:10So there is a lot of data
06:13analysis that goes on here.
06:14But really what's driving this
06:17analysis is the biological and clinical
06:19questions that we want to answer.
06:22And so as you look at
06:25all of this data, and you're
06:28sequencing the genomes
06:30of these cancers and figuring
06:32out which genes are turned on
06:34and which ones are turned off.
06:36What's the next step?
06:38I mean, what people really want to know is,
06:42can you prevent pancreatic cancer
06:44either by causing aberrant genes that
06:47should not be turned on to stay,
06:49not turned on, or turn them off
06:53once they're already there,
06:54so can you prevent cancers from forming?
06:57Or can you use some of what you're
07:00learning in terms of the sequencing
07:03to actually treat these cancers?
07:05So how do you kind of get from
07:08understanding what genes are turned
07:10on and what genes are turned off to
07:13really having something that has
07:16clinical impact?
07:16That's a very good question.
07:18So in the pancreatic cancer
07:20field there are two points of research
07:24that we're trying to tackle.
07:26The first one is early diagnosis and
07:29then the second one is treatment.
07:31My lab in particular
07:33is focused more on the treatment side,
07:35so when we start looking for what
07:38are we going to learn from all
07:40of these sequencing in terms to
07:42really come up with novel ways for
07:46therapeutic approaches for these
07:47patients that desperately need it,
07:49we take an approach where we start
07:51comparing the tumors from patients that
07:54we're very aggressive versus
07:56those tumors from other patients
07:58that were maybe a little bit
08:00more responsive to therapy,
08:01and we try to understand how are these
08:04tumors different at the molecular level.
08:06The reason why we want to understand
08:09differences is because we don't
08:11think that there is a single therapy
08:13that works for all of the tumors.
08:15We know that the mutations that the tumors
08:18carry makes them biologically different.
08:20So what I'm trying to say is,
08:22although they may have the same diagnosis,
08:25at the molecular level,
08:27they're almost kind of oranges and apples,
08:29and so we're trying to dissect out the
08:32therapy that goes for the oranges and
08:34the therapy that goes for the apples.
08:37What my lab is doing differently
08:40from what other labs have done is
08:42we look at the level of turning
08:45on or turning off genes at a
08:47level that it's almost imagine
08:4910 times deeper than what other
08:51scientists have covered so far.
08:53So let me tell you a little
08:56bit of how the genome works.
08:58We used to think that a gene would
09:01get transcribed into this MRNA
09:03and then the MRNA would form a
09:06single protein, and the proteins
09:08to remind everyone are
09:10the functional units of the cell.
09:13There is a pathway by which the
09:16cells actually form a single gene.
09:19They can produce up to 7 different MRNA's,
09:22and each one of these MRNA's can
09:25produce seven different proteins.
09:27So most of the time the scientists
09:31focus on just one of the forms of
09:34those proteins from that single gene,
09:37because probably it is the more abundant one.
09:40But it's not until you start
09:43doing these analysis,
09:44that we do at the MRNA sequencing
09:46level that you start understanding
09:49that they're not only genes that
09:51are being turned on or turned off,
09:54but that when some gene is
09:56turned is being turned on,
09:58maybe it's producing protein A and maybe in
10:01other tumors the gene is still turned on,
10:04but is producing protein B.
10:06A&B are so different,
10:08and this is what my lab tries to dissect out.
10:13A&B are
10:14protein isoforms, and these protein
10:17isoforms as I was mentioning,
10:19may have different functions,
10:22and because previously the
10:24technology or the methods that we
10:27had available could only tell us
10:30is the gene on or not,
10:32now we have the analytical tools in
10:35their technology to say it's been on,
10:38but then it's preferentially expressing
10:41the protein isoform A or the isoform B.
10:45And that uncovers a very new
10:48biology about cancer cells,
10:50but something that had not been seen before.
10:55Why is this important?
10:56It turns out that if we can
10:59dissect this complexity and
11:02diversity in pancreatic cancer,
11:04potentially this can lead us
11:07to new therapies.
11:08Actually, last year my
11:11work group published that pancreatic
11:14cancer is highly susceptible to
11:16any therapy that perturbs this
11:19system of producing protein isoform
11:22A versus protein isoform B,
11:24suggesting that
11:25there is potentially a therapeutic
11:28opportunity to understand more of
11:30these tumors at the protein isoform
11:32level and to generate particular
11:35therapies for these different
11:37proteins that are being expressed.
11:40Let me make sure
11:43I've got this straight.
11:44So you've kind of discovered that
11:47various genes can, when turned on,
11:50will make different isoforms.
11:53And that these isoforms will
11:57respond differently to therapy.
11:59So then the question is,
12:01at the clinic level,
12:03is it possible to distinguish
12:05which are which?
12:07In other words,
12:08if there is a particular therapy that
12:11works better for protein isoform A versus B,
12:15is there a way to know whether a
12:18particular patient is producing
12:20protein isoform A or B?
12:24Yes, so basically we're trying to
12:27get at the point where we develop
12:31an isoform specific therapy and
12:34this will drive personalized therapy.
12:38We have developed in my lab a novel
12:42therapeutic mechanism to be able to switch
12:45and correct these isoform expression.
12:48Let's say that isoform B is
12:51the most
12:54aggressive one,
12:55and it's the most tumorigenic we can
12:57actually correct that isoform and
12:59switch it to the form which
13:02is actually the less aggressive form
13:05and this can drastically impact the
13:07biology and the growth of the tumor.
13:09So we're excited to see what was going
13:12to happen with this new therapy
13:14as we start moving it into clinical trials.
13:18We're going to have to take a short
13:20break for a medical minute,
13:22but we'll get back into that conversation
13:25right after this with my guest
13:28doctor Luisa Escobar-Hoyos.
13:30Support for Yale Cancer Answers
13:32comes from AstraZeneca, working to
13:35eliminate cancer as a cause of death.
13:38Learn more at astrazeneca-us.com.
13:42This is a medical minute
13:44about pancreatic cancer,
13:45which represents about 3% of all cancers
13:48in the US and about 7% of cancer deaths.
13:52Clinical trials are currently being
13:53offered at federally designated
13:55comprehensive Cancer Centers for
13:57the treatment of advanced stage and
14:00metastatic pancreatic cancer using
14:01chemotherapy and other novel therapies.
14:03Folfirinox, a combination of five
14:06different chemotherapies is the latest
14:08advance in the treatment of metastatic
14:10pancreatic cancer and research continues
14:13at centers around the world
14:15looking into targeted therapies.
14:16And a recently discovered marker
14:19HENT one. This has been a medical
14:22minute brought to you as a public
14:24service by Yale Cancer Center.
14:26More information is available at
14:29yalecancercenter.org you're listening
14:30to Connecticut Public Radio.
14:34Welcome back to Yale Cancer Answers.
14:36This is doctor Anees Chagpar
14:39and I'm joined tonight by my guest
14:42doctor Luisa Escobar-Hoyos.
14:44We're talking about her recent research
14:47looking at pancreatic cancers and
14:50before the break she was telling
14:52us about how she's looking at
14:54the genome of these cancers,
14:58finding out that it's not just about
15:01genes being turned on and turned off,
15:04but what protein isoforms those genes
15:06that are turned on actually make?
15:09And some of those may be more
15:12aggressive than others.
15:13Luisa, before we dig more into
15:16your research and the idea that
15:19you could actually switch from
15:21a protein isoform that is more
15:23aggressive to a protein isoform,
15:26that's less aggressive.
15:27Maybe we can take a step back and
15:30you can tell us a little bit more
15:32about why you decided to look at
15:35pancreatic cancer to begin with.
15:36It's certainly one of the most
15:38lethal cancers,
15:39but talk a little bit more about that.
15:43Yes, so it's actually a personal journey.
15:46When I was a PhD student,
15:48I used to study cervical cancer,
15:51and cervical cancer, as we all know,
15:54is now not as lethal because we have
15:57it controlled because we screened
15:59for this disease and there's
16:01less cases that appear in the US.
16:04But after my PhD,
16:06I started thinking that I wanted to put
16:09all my effort to understanding a cancer
16:13that really needed our attention,
16:15and that's when pancreatic
16:16cancer came to my mind.
16:19Several reasons there is a clinical need
16:22that we need to meet in the last 40 years.
16:26We have not changed the five year
16:29survival of pancreatic cancer,
16:31although we have made big progress
16:34in understanding the genetics and
16:36also I wanted to be sure to bring
16:39whatever I had learned from my
16:42understanding of cervical cancer
16:44and apply it into understanding
16:46this more aggressive disease.
16:49And that's when I started training
16:51in pancreatic cancer at Memorial
16:54Sloan Kettering Cancer Center,
16:56under the mentorship of Stephen Leach
17:00a world renowned pancreatic cancer scientist,
17:03so we both kind of wanted to study
17:06a different level of gene expression
17:09by understanding isoform switching
17:11by more specifically understanding
17:14the RNA splicing pathway
17:17in these cancer
17:18cells so you had talked a
17:21little bit before the break about
17:23this isoform switching, but you
17:26just introduced a new term, RNA splicing.
17:30What exactly is that and how does that play
17:34into this whole story?
17:35Yes, so RNA splicing is this pathway
17:38by which the cells decide to produce
17:41one protein isoform versus another,
17:44and this is what allows the
17:46cell to diversify the podium.
17:49So previously we were
17:51talking about 95,000 genes,
17:53and if we can now multiply that
17:55each one of those genes is
17:58going to produce at least five
18:00or seven different proteins.
18:03Imagine how large and versatile
18:05the proteome of a cell becomes.
18:10Why we wanted to study this pathway
18:13or why it came to our attentio,.
18:16it was actually from patient derived data in
18:192016 when I decided to study this cancer.
18:23There were many groups that were
18:25coming up with this hypothesis
18:27that pancreatic cancer comes into
18:30these two molecular subtypes.
18:32And there is one subtype that is more
18:35lethal that different authors coined the
18:38term either basal or squamous subtype.
18:41And then the less lethal form which
18:44the authors called it classical when
18:46we look back into the more aggressive
18:49form this basal squamous molecular
18:52subtype we were seeing that these
18:55tumors have a high expression of all of
18:58these genes that are going to encode
19:02for the splicing machinery
19:05that actually allows the cells to
19:08produce the protein isoforms.
19:11And we started wondering if the reason
19:14why these tumors are so aggressive
19:16is probably because could they be
19:18more versatile in switching from
19:21one isoform to another one,
19:23depending on whatever therapy we
19:25provide to the patient
19:28that they're lancing to the tumor.
19:31Is this why previously we had not
19:33been able to target the right protein
19:36isoforms because we had until this
19:39point ignored the importance of
19:41isoforms in this disease.
19:43That's an interesting concept,
19:46that certain cancer cells may
19:49have this splicing ability that
19:52helps them to switch from a given
19:55protein isoform to another protein
19:58isoform that may be more resistant
20:00to therapy when you look at these.
20:04two different subtypes, are they different
20:06in terms of their aggressiveness?
20:09Even before the therapy?
20:11In other words,
20:13is it that these protein isoforms actually
20:16cause differences in the biology of the
20:19aggressiveness of the tumor itself,
20:21or is it really this ability to react
20:24to the treatment with a different
20:27isoform that is more resistant?
20:30We think
20:31it's actually both.
20:33We think that this
20:34capability of being plastic,
20:36it appears in naive tumors,
20:39so meaning before any treatment.
20:42But it also gets used once you challenge
20:45the tumor with different therapies,
20:48so we think that this is kind
20:51of an active pathway
20:53that it allows the cells to transform
20:57and to become cancer cells during
21:00the pathogenesis and after the
21:02pathogenesis during treatment time.
21:04You were mentioning that you've
21:07come up with a way to block
21:10that splicing, block that switching.
21:13So that if you prevent the
21:15cancer cell from actually
21:16switching to a different isoform,
21:19then potentially that cell is going
21:21to be more responsive to therapy,
21:23or at least would not be able to
21:26produce a protein isoform that
21:28would be resistant to therapy. Is
21:30that right?
21:32Yes, what we have learned
21:34so far from these therapies,
21:37that is actually very potent
21:39that these cancer cells do not,
21:41whenever you correct a splicing
21:43defect that they have in that they need
21:47to survive as soon as you corrected
21:50the cells become more sensitive
21:53to chemotherapeutic agents and or
21:55they just die on their own because
21:59they cannot tolerate losing that
22:01expression of a particular isoforms.
22:05The next question obviously
22:07is how exactly does that happen?
22:09I mean, because this splicing
22:12mechanism is presumably something
22:14that is intrinsic to that tumor cell.
22:16So in order to stop it,
22:19you would need to get something into
22:21that tumor cell that actually stops
22:24something that it intrinsically has.
22:26How do you do that?
22:28And has that been tested in
22:31humans?
22:34The cell in order to switch from
22:37one isoform to another one,
22:39the MRNA's have different sequences
22:42or different signals that
22:45is going to tell a cell produce
22:47isoform A or produce isoform B.
22:49Once we have identified which
22:52isoform we want to target.
22:54What we do is we introduce these
22:57small pieces of RNA into
22:59a cell and what we're going to
23:02do is we're going to block
23:05signals that usually the
23:06cancer cell would read to produce
23:09the most lethal isoform,
23:11and we're going to fool it to
23:14make sure that it doesn't see it.
23:16To mask these sites and
23:19force it to produce the other form and
23:22this therapy because of the way that
23:25it works, we called it SHOT.
23:28Actually giving SHOT to the
23:31cancer cells and shot stands for
23:34Splicing-Hit Oligonucleotide Therapy.
23:36So far we have not tested it in humans.
23:40All of our data comes so far
23:43from patient cells.
23:45Tumor patient tumor cells
23:46that we grow in the lab.
23:49We also have tested this in our
23:52genetically engineered mouse models
23:54and all of that has produced
23:56the preliminary data to start.
23:58Hopefully launching a clinical trial
24:00in the short future in the patients.
24:04So the next question is when you
24:07have this mechanism, this shot that
24:10can block this splicing mechanism,
24:12presumably you're giving it
24:15whether it's IV or orally,
24:19somehow you're trying to
24:21get this into tumor cells.
24:24Does it get into normal cells
24:27and does it have any effect
24:29on the normal cells as well?
24:31Or do normal cells not have
24:33this splicing mechanism?
24:35That's a very important question,
24:37so far the therapy that we
24:40like, the first phase of this therapy,
24:43we know that it's a specific for
24:45cancer cells because it's only
24:48going to correct splicing defect
24:50that appears only on cancer cells.
24:53It still gets into the normal cells.
24:56But it's not active there.
25:00because the splicing defect is not present.
25:03So far we have managed to introduce
25:07the therapy into the cancer cells by
25:10directly injecting into the tumors
25:12of mice what we are excited right
25:15now is that we're going to start
25:18coupling SHOT with another therapy
25:21delivery technology that has been
25:23developed here at Yale and is actually
25:27currently under clinical trial testing
25:29called FLIP and FLIP is almost like a
25:32bio syringe that is going to carry shot
25:35and once said it lands into the tumor
25:38that has this particularly low pH,
25:41at that time it will convert into a syringe.
25:44It will introduce shot into the
25:47cells that are in that
25:50tumor microenvironment.
25:51So in that tumor microenvironment
25:53you have cancer cells and you
25:56have cells that are non cancerous.
25:58But the specificity comes that shot
26:00would only be able to correct splicing
26:03defects in cells that have it,
26:06and those splicing defects are
26:08only present in cancer cells.
26:10So I think the combination of flip and shot
26:12is going to be highly specific
26:15for tumor cells is going to be highly
26:19specific for splicing defects that
26:21we know are important for these cells
26:23and is going to decrease the amount
26:26of side effects because this therapy
26:29is so specific.
26:31One question is, if shot
26:33is so specific based on the fact
26:37that this slicing mechanism
26:39only exists in cancer cells,
26:41then I guess the next question is,
26:44do you really need flip to kind of
26:48take it to where the cancer cells are,
26:51which is a low pH area?
26:54Or can you just inject shot
26:57systemically and know that
26:59even if it were to circulate around,
27:01and get absorbed by other cells that
27:04it really wouldn't cause any harm,
27:06the only harm it would cause
27:08is in the tumor cells,
27:10or is the idea behind flip that
27:12you would decrease the amount of
27:15shot that you would need so that
27:17you could more accurately target
27:19it to where the tumor actually is.
27:22It's actually the latter.
27:23This is the way that we can increase the
27:26amount of dose of shot that is going
27:29to go directly into the cancer cells.
27:32Because if we just put shot systemically
27:34without a delivery technology,
27:36it will start getting word out and
27:38the concentration is going to drop
27:40and by the time the little bit that
27:43reaches the tumor it might be too low
27:46to have a biological impact.
27:48And so has this
27:50combination of flip and shot
27:52been tried in mouse models?
27:54Were actually testing it and this is part
27:56of the one of the reasons why I wanted to
27:59come to Yale because I wanted to combine
28:03a very exciting therapy with other
28:06delivery technologies that were being
28:09developed here specifically for
28:11these therapies that
28:14modify the way that the cells
28:16express proteins and turn on genes,
28:19and so we are hoping that now that
28:22the research is ramping up after
28:25COVID that we can start testing,
28:28we cannot wait to collaborate and
28:30we're already starting to synthesize
28:32the shot in combination with flip.
28:36Doctor Luisa Escobar-Hoyos is an
28:38assistant professor of therapeutic
28:40radiology at the Yale School of Medicine.
28:42If you have questions,
28:44the address is canceranswers@yale.edu
28:46and past editions of the program
28:48are available in audio and written
28:50form at yalecancercenter.org.
28:51We hope you'll join us next week to
28:54learn more about the fight against
28:57cancer here on Connecticut Public Radio.