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Pancreatic Cancer Research

May 10, 2021
  • 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.