Genomic Causes of Cancer Progression and Therapeutic Vulnerability

December 13, 2021

Information

December 12, 2021

Yale Cancer Center

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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
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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.