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Genomic Causes of Cancer Progression and Therapeutic Vulnerability

December 13, 2021
  • 00:00Funding for Yale Cancer Answers
  • 00:02is provided by Smilow Cancer
  • 00:04Hospital and Astra Zeneca.
  • 00:08Welcome to Yale Cancer Answers with
  • 00:10your host doctor Anees Chagpar.
  • 00:12Yale Cancer Answers features the
  • 00:14latest information on cancer care by
  • 00:16welcoming oncologists and specialists
  • 00:17who are on the forefront of the
  • 00:20battle to fight cancer. This week,
  • 00:22it's a conversation about genomic causes
  • 00:24of cancer progression and therapeutic
  • 00:26vulnerabilities with Doctor Jason Sheltzer.
  • 00:27Dr Sheltzer is an
  • 00:29assistant professor of surgery and
  • 00:31oncology at the Yale School of
  • 00:33Medicine where Doctor Chagpar is
  • 00:35a professor of surgical oncology.
  • 00:38Jason, maybe we can start off by
  • 00:39you telling us a little bit about
  • 00:41yourself and what exactly you do.
  • 00:43Sure, so despite my departmental affiliation
  • 00:45I am neither a surgeon nor an oncologist.
  • 00:49I am a basic science researcher.
  • 00:52I have a PhD in molecular biology
  • 00:55and my lab studies the genetic basis
  • 00:58of cancer development and cancer
  • 01:01therapeutic responses from a basic
  • 01:04or a non clinical perspective.
  • 01:08That sounds pretty interesting,
  • 01:09but it also sounds pretty broad.
  • 01:11We talk a lot on
  • 01:15this show about the genomic and
  • 01:17genetic underpinnings of cancer,
  • 01:19so tell us a little bit
  • 01:20more about your research,
  • 01:22sure, so overall, I think that it is a
  • 01:26really remarkable time in cancer biology.
  • 01:29There are a ton of exciting
  • 01:32advances happening at Yale and at
  • 01:35institutions around the world,
  • 01:36and there are just rapid advances
  • 01:38in so many areas that are really
  • 01:41directly contributing to patient care.
  • 01:43In my own lab, were interested in using
  • 01:46different genetic techniques to model
  • 01:49certain alterations in chromosomes
  • 01:51that you commonly see in cancer.
  • 01:54So in cancer cells most normal cells
  • 01:57in your body have 46 chromosomes,
  • 02:0023 pairs of chromosomes,
  • 02:02but for some reason cancer cells almost
  • 02:04all have the wrong number of chromosomes.
  • 02:06Cancer cells have 47 chromosomes or
  • 02:0948 chromosomes, or 140 chromosomes,
  • 02:11and no one really.
  • 02:13Understands how that happens or why?
  • 02:16Why that contributes to tumor
  • 02:18growth and my lab tries to generate
  • 02:21techniques to model these chromosome
  • 02:23changes so we can understand how
  • 02:25they contribute to cancer.
  • 02:28OK, so I guess there's a few
  • 02:31questions to unpack there.
  • 02:33The first is why do cancer cells have
  • 02:36a different number of chromosomes
  • 02:39and what impact does that have
  • 02:41on cancer development, right?
  • 02:44So there are two schools of thought there,
  • 02:46so on one hand, some people think that
  • 02:49this is just like an accident of cancer.
  • 02:52Cancer cells do a lot of things wrong.
  • 02:55They're they're very genomically unstable.
  • 02:57They have all sorts of errors that occur
  • 03:00during the cell cycle, and so some
  • 03:03scientists think that the aneuploidy,
  • 03:06which is another word for the chromosome copy
  • 03:09number alterations that we see in cancer.
  • 03:12Some scientists think that this
  • 03:14aneuploidy is just kind of a byproduct
  • 03:16of things going wrong in cancer,
  • 03:18and that it doesn't really
  • 03:20have a functional importance.
  • 03:21On the other hand,
  • 03:23other scientists believe that these
  • 03:26chromosome copy number alterations are
  • 03:28directly influencing the development
  • 03:31and the progression of cancer and the
  • 03:34idea there is that these chromosome
  • 03:37copy number changes are influencing
  • 03:39the number of copies of a gene you
  • 03:43have in a cell instead of having
  • 03:45two copies of a gene like you would
  • 03:48in most normal cells in your body,
  • 03:50you may have three copies.
  • 03:52Or four copies or 25 copies of a gene.
  • 03:55And if that gene has tumor
  • 03:58promoting properties,
  • 03:59then having 25 copies of that gene
  • 04:02might directly contribute to cancer.
  • 04:05So so a few questions.
  • 04:07The first question is there
  • 04:10are some congenital anomalies,
  • 04:13some congenital conditions.
  • 04:14So I'm thinking about things
  • 04:17like Klinefelter syndrome or
  • 04:19Down syndrome where people
  • 04:22may have an altered number of
  • 04:26copies of certain chromosomes.
  • 04:28Does that mean that those people
  • 04:30by definition are at increased
  • 04:31risk of developing cancer,
  • 04:34yeah? It's it's a really
  • 04:37interesting and important question.
  • 04:39Down syndrome is a developmental
  • 04:42disability caused by having
  • 04:44three copies of chromosome 21.
  • 04:47It's the most common genetic cause
  • 04:50of developmental disability in EU.
  • 04:53S individuals with Down syndrome
  • 04:56have a significantly greater risk
  • 04:59of developing leukemia and other
  • 05:01blood cancers during their lifetime.
  • 05:04At the same time, for reasons that
  • 05:06I think are very poorly understood,
  • 05:09individuals with Down syndrome actually
  • 05:11have a significantly decreased risk
  • 05:14of developing most solid cancers.
  • 05:17Individuals with Down syndrome
  • 05:18have lower rates of colon cancer,
  • 05:21breast cancer, brain cancer,
  • 05:23Melanoma,
  • 05:24and I think that that discrepancy
  • 05:26is is very poorly understood,
  • 05:29and so how do you square that
  • 05:32with the concept of the thought?
  • 05:34At least the one school of
  • 05:36thought of some scientists.
  • 05:38As you point out that having a.
  • 05:41Discrepant number of copies of a chromosome.
  • 05:44So if you've got more copies than
  • 05:46you're producing more gene products,
  • 05:49more proteins.
  • 05:49Cancer cells are more likely to go
  • 05:52awry that predisposes to cancer,
  • 05:55whereas these people have
  • 05:56a lower risk of cancer.
  • 05:59How do you square those two phenomena?
  • 06:02Yeah, that's a terrific question.
  • 06:04So in your cells,
  • 06:06not all chromosomes are equivalent.
  • 06:09Not all genes are equivalent.
  • 06:11There are some genes.
  • 06:12That when you have them
  • 06:14present in extra copies,
  • 06:15they may promote cancer and
  • 06:17there are other genes that when
  • 06:19you have them in extra copies,
  • 06:20they may actually suppress cancer.
  • 06:22They prevent the development of
  • 06:24cancer and there's a further layer of
  • 06:28complication in that different tissues
  • 06:30in your body are different as well,
  • 06:32and so a gene that has a
  • 06:35certain function in blood cells.
  • 06:36It may have a different function,
  • 06:38or it may have no function
  • 06:41whatsoever in mammary gland cells.
  • 06:43Or in neurons,
  • 06:44or in any other cell type in your body.
  • 06:46And so the current commonly accepted
  • 06:50explanation for the Down syndrome
  • 06:53cancer phenomenon is that there
  • 06:55are genes on chromosome 21 which
  • 06:58promote the development of cancer
  • 07:00in blood cells which promote
  • 07:02the development of leukemias,
  • 07:04which are what are commonly observed
  • 07:06in individuals with Down syndrome.
  • 07:08But these genes or other genes
  • 07:11on chromosome 21.
  • 07:13May actually suppress the development
  • 07:15of cancer in other tissues,
  • 07:17and it's a really strange phenomenon,
  • 07:21and the relationship between the
  • 07:22copy number of these genes and the
  • 07:25copy number of genes in general
  • 07:26and the development of cancer.
  • 07:28I think there's a lot more to explore
  • 07:30there that science doesn't yet know.
  • 07:33And I guess the other question is if
  • 07:36I understood you correctly earlier,
  • 07:39you were saying that this copy
  • 07:41number phenomenon is is quite
  • 07:42common in cancer, is that right?
  • 07:44Yep, about 90 to 95% of cancers have the
  • 07:49wrong number of chromosomes in them.
  • 07:51So my next question has to do with this.
  • 07:56Is it that there's the wrong
  • 07:58number of copies of a particular
  • 08:01chromosome in the cancer cell?
  • 08:03Or is this a germline phenomenon,
  • 08:06so we know that for example in Down
  • 08:09syndrome it's a germline phenomenon.
  • 08:11You have an extra copy of chromosome
  • 08:1421 in all of the cells in your body,
  • 08:17whereas it seems to me that you know
  • 08:20if we know that most cancers have this.
  • 08:23Most cancers are also going to
  • 08:26occur in people who do not have any
  • 08:29kind of aneuploidy. Is that right?
  • 08:31So so it is it more that cancer cells?
  • 08:35Acquire extra copies as they move
  • 08:39along their cancer Genesis pathway.
  • 08:42Yes,
  • 08:43so I think that we can say that
  • 08:46most of the chromosome alterations
  • 08:48that occur in cancer are cymatic
  • 08:51or they occur during the body over
  • 08:54a lifetime and are not germ line.
  • 08:56That is, you aren't born with them,
  • 08:59but they instead accumulate
  • 09:01overtime more broadly.
  • 09:04A lot of research has been done
  • 09:08indicating how different mutations or
  • 09:10single base pair changes can occur over
  • 09:13a person's lifetime and contribute
  • 09:16to their cancer risk overtime.
  • 09:19In addition to these point
  • 09:21mutations which contribute to cancer
  • 09:23development and occur overtime,
  • 09:25there's increasing evidence
  • 09:27that overtime your cells will
  • 09:29accumulate more aneuploidy or more
  • 09:32chromosome copy number errors.
  • 09:34As well,
  • 09:35so if you look in cells that are
  • 09:37isolated from say an 80 year old
  • 09:39person and compare them to normal
  • 09:41cells that are isolated from say 20
  • 09:44year old person in general the 80
  • 09:46year old will have significantly more
  • 09:49aneuploidy or chromosomal errors in
  • 09:52their tissue than the 20 year old,
  • 09:55and this may be one of the unexplored
  • 09:58or underexplored causes of why
  • 10:02cancer incidence increases with age.
  • 10:05Because of these somatic chromosomal
  • 10:07alterations that are developed overtime
  • 10:10and so is it. The concept that if
  • 10:13you could somehow reverse that
  • 10:15process or stop that process
  • 10:18such that people did not acquire
  • 10:20aneuploidy as they grew older,
  • 10:23that you could actually
  • 10:26potentially stop certain cancers.
  • 10:29Absolutely, that would be an incredibly
  • 10:33exciting cancer prevention strategy.
  • 10:35If it was true, there is and we just
  • 10:39don't yet know again to contrast
  • 10:42the the research on aneuploidy or
  • 10:45chromosomal changes with the research
  • 10:48on mutations and DNA base pair changes.
  • 10:52A lot of research has been done trying
  • 10:55to develop strategies to delay the
  • 10:57development of point mutations over age.
  • 11:00People have talked about antioxidants and
  • 11:03vitamin C as some potential strategies.
  • 11:06I don't think there's there's good
  • 11:07evidence for their strategies,
  • 11:08but those are some of the strategies
  • 11:11that have been described for the
  • 11:13prevention of point mutations for
  • 11:15the prevention of chromosome errors.
  • 11:17Almost nothing is known,
  • 11:19and this is absolutely something that
  • 11:21my lab plans to study at Yale to see
  • 11:24if we can prevent the development
  • 11:26of aneuploidy overtime,
  • 11:27and if that would subsequently slow
  • 11:30or delay the development of cancer.
  • 11:34So tell us more about about that.
  • 11:36How do you plan on doing those experiments,
  • 11:39and what might we have to look
  • 11:41forward to in the future? Yeah,
  • 11:44there is a lot that we are planning to do.
  • 11:48In general, I think that there are certain
  • 11:52proteins that are known to control
  • 11:55the process of chromosome segregation.
  • 11:58These were proteins that were first
  • 12:01discovered in simple single celled organisms.
  • 12:04Like budding yeast Saccharomyces service,
  • 12:07yeah, the basic process of chromosome
  • 12:09segregation was worked out in in these
  • 12:12simple organisms and then later research
  • 12:15demonstrated that these same genes
  • 12:17that function in simple single celled
  • 12:19eukaryotic organisms also function
  • 12:21in human cells and in cancer cells
  • 12:24to control chromosome segregation.
  • 12:26And so one of our ideas is to take some
  • 12:29of these genes and then manipulate
  • 12:31their expression.
  • 12:32That is if you have genes whose
  • 12:34role in the cell?
  • 12:35Is to protect the fidelity
  • 12:38of chromosome segregation,
  • 12:39then maybe over expressing some of
  • 12:41these genes would further protect the
  • 12:44fidelity of chromosome segregation
  • 12:45and decrease the number of errors
  • 12:48that occur during aging.
  • 12:49That's some of the research that
  • 12:50we plan to do in my lab,
  • 12:53and so when you talk about chromosome
  • 12:56segregation just to remember back
  • 12:58to you know junior high biology,
  • 13:01that's that's really when the the cells are
  • 13:04replicating and they're going to divide.
  • 13:07That your body kind of the cell puts
  • 13:09half the chromosomes in one daughter
  • 13:11cell and half the chromosomes and the
  • 13:14other daughter cell is that right?
  • 13:16Yep, the the magic of the cell cycle
  • 13:19and so and so is the concept of aneuploidy.
  • 13:22When you say that there may be a lack
  • 13:25of fidelity that that segregation
  • 13:28processes where you know they may
  • 13:31put 2047 chromosomes in one cell
  • 13:35and and and 45. And the other.
  • 13:39Yep, so during the cell cycle
  • 13:42you have 46 chromosomes.
  • 13:43Normally in most cells in your
  • 13:46body during the cell cycle,
  • 13:48each chromosome gets replicated and so
  • 13:51you wind up with 92 chromosomes instead
  • 13:55of 46 for a short period of time,
  • 13:58and then those 92 chromosomes need
  • 14:00to divide equally such that one
  • 14:03daughter cell gets 46 chromosomes
  • 14:05and the other daughter cell.
  • 14:07Also gets 46 chromosomes and if
  • 14:10you have an error in that process
  • 14:13and one daughter cell gets 47
  • 14:15and the other gets 45 instead,
  • 14:18that that produces aneuploidy,
  • 14:19that's a chromosome segregation error
  • 14:21that we think can have pretty profound
  • 14:24consequences for cancer development.
  • 14:27Well, we're going to take a short
  • 14:29break and learn more about the
  • 14:31causes of cancer progression and
  • 14:34therapeutic vulnerability right
  • 14:35after we take a short break.
  • 14:37For a medical minute,
  • 14:39please stay tuned to learn more
  • 14:41with my guest Doctor Jason Shelter
  • 14:43funding for Yale Cancer Answers
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  • 14:49hope for people living with cancer.
  • 14:51More information at Astra Zeneca Dash us.com.
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  • 15:01year and in Connecticut alone
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  • 15:11quitting even after decades of use
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  • 15:27Survivors more hope than they
  • 15:29have ever had before.
  • 15:30Clinical trials are currently
  • 15:32underway at federally designated
  • 15:34Comprehensive cancer centers,
  • 15:36such as the battle two trial at
  • 15:38Yale Cancer Center and Smilow
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  • 15:49More information is available at
  • 15:52yalecancercenter.org you're listening
  • 15:53to Connecticut Public Radio.
  • 15:55Welcome
  • 15:56back to Yale Cancer answers.
  • 15:57This is doctor in East Tag part
  • 15:59and I'm joined tonight by my
  • 16:01guest Doctor Jason Shelter.
  • 16:03We're learning about his research
  • 16:05into the genomic causes of cancer
  • 16:07progression and before the break
  • 16:09Jason you were talking a lot
  • 16:12about this concept of aneuploidy.
  • 16:13The the idea that having an
  • 16:16incorrect number of chromosomes can
  • 16:18predispose to cancer and some of
  • 16:20the work that your lab is planning
  • 16:23on doing to kind of address.
  • 16:25That and and look at whether that is a
  • 16:28potential target for cancer prevention.
  • 16:30But are there other mechanisms of
  • 16:34cancer development outside of aneuploidy,
  • 16:38that your lab is also looking at?
  • 16:40Yep, so in addition to the chromosome
  • 16:43errors that occur in cancer,
  • 16:45there are single base pair changes
  • 16:48point mutations in the sequence
  • 16:51of the chromosomes themselves,
  • 16:53which have a fundamental role in
  • 16:56driving cancer development and at
  • 16:58the same time which also create
  • 17:01potential therapeutic vulnerabilities
  • 17:03or potential ways for scientists
  • 17:05and clinicians to treat cancer so
  • 17:08so tell us more about that.
  • 17:09Maybe give us an example of some
  • 17:10of the things that your lab.
  • 17:12Is working on in that vein,
  • 17:14Yep, so there has been an absolute
  • 17:17revolution in cancer therapy over
  • 17:19the past 10 to 20 years previously.
  • 17:22For most of the 20th century,
  • 17:24the standard way to treat cancer was
  • 17:27slash and burn was to cut it out of
  • 17:30your body through surgery and then
  • 17:33to burn any cells that remained
  • 17:35with the use of radiation which
  • 17:37does kill cancer cells but can have
  • 17:40very profound side effects as well.
  • 17:42Or with chemotherapy agents,
  • 17:44which again can kill cancer cells,
  • 17:46but have some pretty significant side
  • 17:48effects as well in the past 20 years,
  • 17:51there's been a revolution in the
  • 17:53development of what are called
  • 17:55targeted therapies.
  • 17:56That is, these are drugs,
  • 17:58which instead of just nonspecifically
  • 18:02killing kind of all cells that it encounters,
  • 18:05targeted therapies are designed
  • 18:07to inhibit specific proteins that
  • 18:10are expressed by cancer cells.
  • 18:13In order to eliminate cancer
  • 18:15cells while leaving normal tissue
  • 18:18unharmed or relatively unharmed,
  • 18:20my lab uses a genetic tool called
  • 18:24crisper and crisper is a new tool for
  • 18:28genome engineering that was recently
  • 18:31developed just in the past seven or so years,
  • 18:35and it allows you to make very precise
  • 18:39modifications in the in any cells
  • 18:42that you're interested in studying.
  • 18:44So using CRISPR you can go into a
  • 18:47cancer cell or a normal cell growing
  • 18:49in a Petri dish or growing in a mouse.
  • 18:52And then you can cut out a gene of interest.
  • 18:55Or you can introduce a mutation
  • 18:58into a gene of interest and then
  • 19:00study how cutting out that gene
  • 19:03or introducing a mutation affects
  • 19:06the biology of those cancer cells.
  • 19:09We can link this then to the question of
  • 19:12targeted therapy because we can delete.
  • 19:14A gene in cancer cells using crisper.
  • 19:17That is,
  • 19:17we can knock it out from cancer
  • 19:19cells and then we can ask whether
  • 19:21these cancer cells live or whether
  • 19:23these cancer cells die.
  • 19:24So just out of curiosity,
  • 19:27when you said that we couldn't do this
  • 19:29before CRISPR in mammalian cells,
  • 19:31we could only do it in single
  • 19:34celled organisms. Why is that?
  • 19:36What is how exactly does CRISPR work to
  • 19:40allow you to do this in mammalian cells?
  • 19:42What's the difference in
  • 19:44single celled eukaryotes?
  • 19:46You can introduce foreign genetic
  • 19:49material quite easy and the cells will
  • 19:54oftentimes incorporate the foreign
  • 19:56genetic material into their own DNA.
  • 20:00They randomly will pick up
  • 20:02DNA from the environment and
  • 20:04incorporate it into their genomes,
  • 20:06and that's in fact unrelated to what I study.
  • 20:09But one of the causes of the problem of
  • 20:13antibiotic resistance among bacteria.
  • 20:16And among eukaryotic parasites
  • 20:18that they have this habit of just
  • 20:21picking up random DNA and taking it,
  • 20:23scientists have taken advantage of
  • 20:26that process in order to genomically
  • 20:29modify these single celled eukaryotes
  • 20:32to study them in the lab.
  • 20:35In the context of cancer,
  • 20:37cancer cells normal cells don't
  • 20:39really do that.
  • 20:41Any one of us could take a bath
  • 20:43in a pool full of DNA,
  • 20:45and we would not start expressing random
  • 20:48things from the DNA that we're swimming in.
  • 20:51That just isn't how mammalian cells work.
  • 20:54Crisper is a DNA cutting enzyme,
  • 20:59and so while you normally wouldn't just
  • 21:03randomly change or randomly modify DNA.
  • 21:07In a eukaryote in a mammalian cell.
  • 21:10Because CRISPR is a DNA cutting enzyme
  • 21:12we can use it in order to cut the DNA
  • 21:15in a certain place in a defined manner,
  • 21:18which allows scientists to make
  • 21:20these modifications and cancer
  • 21:22cells that we couldn't before.
  • 21:24When you use crisper say in in a mouse,
  • 21:29does it affect all the cells in that
  • 21:32mouse or is it a given cell or is
  • 21:35it a few cells like how diffuse?
  • 21:37Is the effect that you can
  • 21:40have on a given gene? Yeah,
  • 21:43so it depends on how you use it
  • 21:46and how you plan your experiment.
  • 21:49CRISPER is useful both as a research
  • 21:53tool and itself as a potential
  • 21:56therapeutic modality in the future.
  • 21:59So in my lab we use CRISPR
  • 22:01as a research tool.
  • 22:02We want to make certain modifications
  • 22:04in cancer cells in order to
  • 22:06respond to see how cancer cells.
  • 22:08Respond in addition to that,
  • 22:11when you start thinking about using
  • 22:13crisper in a mouse or in an Organism,
  • 22:15there are potential therapeutic
  • 22:17uses for CRISPR as well,
  • 22:19say to treat genetic diseases
  • 22:21or to treat cancer itself.
  • 22:23This is much more preliminary.
  • 22:25There is a lot of work to do there,
  • 22:28but for instance in some of the clinical
  • 22:31trials that have been done and in some
  • 22:33of the mouse work that has been done,
  • 22:35the liver is the organ in your body.
  • 22:39That generally detoxifies
  • 22:40foreign matter that you receive,
  • 22:44and so if you just inject CRISPR
  • 22:47particles into a mouse's body,
  • 22:50or into a human body,
  • 22:52they oftentimes go to the
  • 22:54liver and they will genetically
  • 22:55modify cells in the liver.
  • 22:58So so tell us a little bit more about
  • 23:01you know you mentioned that your lab
  • 23:04is using CRISPR to kind of figure out
  • 23:07targets for potential cancer therapeutics.
  • 23:12How do you take that to the next level
  • 23:15and figure out what are those targets?
  • 23:18How you might design drugs against them,
  • 23:21and tell us a little bit more about
  • 23:23the potential for this in the future.
  • 23:26Yep, so 22,000 genes in the genome.
  • 23:29Some of them may make good targets
  • 23:31for cancer, and some of them may
  • 23:33not make good targets for cancer.
  • 23:35The first step in this process is the
  • 23:37one that my lab is most active in.
  • 23:39We try and use CRISPR to identify
  • 23:42the genes and cancer cells that
  • 23:44are required for cancer growth.
  • 23:47If you can eliminate a gene with CRISPR
  • 23:50and it causes cancer cells to die,
  • 23:53then that gene might be a promising
  • 23:56target for therapeutic development.
  • 23:57Unfortunately,
  • 23:58when it comes to actually
  • 24:01developing a drug against that gene,
  • 24:04that is a complicated process that we
  • 24:07are still learning a whole lot about.
  • 24:10There are some genes in the
  • 24:12genome which code for proteins.
  • 24:15Proteins are the functional part of the cell.
  • 24:17The part that actually does the work.
  • 24:19There are some proteins that are
  • 24:22basically like big greasy balls.
  • 24:24They just are greasy and they don't
  • 24:26bind to anything and they're very
  • 24:28hard for something to latch onto.
  • 24:31And something that's you know big
  • 24:33and greasy like that just doesn't
  • 24:35make a good drug target because there
  • 24:38is nothing for a drug to bind onto.
  • 24:41What you really want for a drug
  • 24:43target is you want a protein that's
  • 24:45the part of the cell that that
  • 24:47actually does the work that has say.
  • 24:51Various binding pockets on it or
  • 24:54holes in it where you can design a
  • 24:57small molecule compound to actually
  • 24:59bind in that pocket and then inhibit
  • 25:02that proteins function.
  • 25:03So there are some genes that are
  • 25:05required for cancer growth but that
  • 25:06are very very hard to generate drugs
  • 25:08against because they're just greasy
  • 25:10and there's nothing to bind onto.
  • 25:11And then there are other proteins
  • 25:14and cells that are possible for
  • 25:16you to design drugs against and
  • 25:18we want to see if we can identify
  • 25:20those proteins in particular.
  • 25:23And so you know, this kind of brings
  • 25:25me back to the question that we were
  • 25:27talking about earlier in terms of,
  • 25:29you know I I get the whole concept of
  • 25:32crisper being used to look at jeans
  • 25:34that you can specifically target
  • 25:36to see whether they would be a good
  • 25:39target or a not so good target.
  • 25:41But ultimately when you're looking
  • 25:43at developing drugs,
  • 25:44it sounds like you're developing
  • 25:47drugs against proteins.
  • 25:48Which brings me back to if you know
  • 25:51that a particular gene is involved in cancer,
  • 25:54Genesis, uhm, why not target the gene so,
  • 25:58especially if crisper is very
  • 26:01specific for a particular gene,
  • 26:04do you think that that I,
  • 26:06I realize you said that earlier
  • 26:08that this is very preliminary,
  • 26:09but do you think that there will be a
  • 26:13role for that kind of gene editing?
  • 26:16And can you really do that in?
  • 26:18A fully mature adult Organism?
  • 26:21Yeah, that's a great question and I
  • 26:25think that you're just thinking about
  • 26:2725 years in the future right now.
  • 26:30So like I to go back to the
  • 26:33analogy or the thought experiment
  • 26:36that I previously mentioned.
  • 26:38If you or I were to dive
  • 26:41into a bath full of DNA,
  • 26:44nothing would really happen to us because
  • 26:47mammalian cells do not readily take.
  • 26:50Foreign DNA DNA,
  • 26:52as itself is highly charged
  • 26:56deoxyribonucleic acid.
  • 26:57It it it is an acid and it it won't just
  • 27:02normally pass from outside ourselves
  • 27:04or outside our body into our body.
  • 27:07In order to have.
  • 27:11To have crisper actually enter our body,
  • 27:15you need to develop some approach
  • 27:18that allows a very big macromolecule
  • 27:21with a nucleic acid component,
  • 27:24because part of crisper
  • 27:26is is ribonucleic acid.
  • 27:27Actually you need to get that from
  • 27:30out of your body into your body and
  • 27:33into cancer cells and that problem
  • 27:35of delivery getting the crisper
  • 27:37where you want it is a pretty
  • 27:39significant challenge right now.
  • 27:42With current targeted therapies and cancer,
  • 27:44these are small molecules.
  • 27:46You know, maybe 50 atoms,
  • 27:49a hundred 150 atoms and they will pass
  • 27:53through cell membranes quite readily,
  • 27:56and so it's much easier to get them
  • 27:58to cancer cells where they can do the
  • 28:01work of inhibiting cancer cell growth.
  • 28:03At the same time as we develop
  • 28:07improved techniques to get nucleic
  • 28:10acids into the body,
  • 28:13for instance.
  • 28:14People I'm sure are familiar with
  • 28:16the M RNA vaccines for COVID-19,
  • 28:19which involved getting nucleic acids
  • 28:21into cells in your body as those
  • 28:25types of approaches for delivery
  • 28:27improve will have ways to use
  • 28:29CRISPR for cancer treatment as well.
  • 28:32Doctor Jason Shelter is an assistant
  • 28:35professor of surgery and oncology
  • 28:36at the Yale School of Medicine.
  • 28:38If you have questions,
  • 28:40the address is cancer answers at
  • 28:42yale.edu and past editions of the
  • 28:44program are available in audio and
  • 28:46written form at Yale Cancer Center Org.
  • 28:49We hope you'll join us next week to
  • 28:51learn more about the fight against
  • 28:52cancer here on Connecticut Public
  • 28:54radio funding for Yale Cancer
  • 28:56Answers is provided by Smilow
  • 28:57Cancer Hospital and Astra Zeneca.