The Role of DNA Repair and Damage in Cancer

Transcript

00:00 --> 00:01Funding for Yale Cancer Answers
00:01 --> 00:03is provided by Smilow Cancer
00:03 --> 00:05Hospital and AstraZeneca.
00:07 --> 00:09Welcome to Yale Cancer Answers with
00:09 --> 00:11your host doctor Anees Chagpar.
00:11 --> 00:13Yale Cancer Answers features the
00:13 --> 00:16latest information on cancer care by
00:16 --> 00:17welcoming oncologists and specialists
00:17 --> 00:20who are on the forefront of the
00:20 --> 00:22battle to fight cancer. This week,
00:22 --> 00:24it's a conversation about DNA
00:24 --> 00:26repair with Doctor Megan King.
00:26 --> 00:28Doctor King is an associate professor
00:28 --> 00:30of cell biology and of molecular,
00:30 --> 00:32cellular, and developmental biology
00:32 --> 00:34at the Yale School of Medicine,
00:34 --> 00:36where Doctor Chagpar is a
00:36 --> 00:37professor of surgical oncology.
00:39 --> 00:42Megan, maybe we can start off with you
00:42 --> 00:44telling us a little bit about yourself
00:44 --> 00:47and about your research and how you got
00:47 --> 00:49involved in this research project to
00:49 --> 00:50begin with.
00:50 --> 00:52Yeah, so it's very interesting thinking
00:52 --> 00:54back to what drew me towards science.
00:54 --> 00:56I'm from a family of engineers,
00:56 --> 00:59actually including both of my parents,
00:59 --> 01:01but I always gravitated towards science,
01:01 --> 01:04and in particular as a high school student,
01:04 --> 01:06I took anatomy and Physiology,
01:06 --> 01:07and it was actually the
01:07 --> 01:09section of my textbook
01:09 --> 01:11on cancer that really provided for me,
01:11 --> 01:14I think the first kind of window into
01:14 --> 01:16how a scientist could have a positive
01:16 --> 01:19impact on human health in a way that was
01:19 --> 01:22different from becoming a medical doctor,
01:22 --> 01:24which I think all of us are a
01:24 --> 01:26little bit more familiar with,
01:26 --> 01:27certainly as children.
01:27 --> 01:29And so I've been reflecting on
01:29 --> 01:31that recently because it's been a
01:31 --> 01:33bit of a circuitous route that's
01:33 --> 01:35brought me back to Cancer Research.
01:35 --> 01:37I really trended towards very
01:37 --> 01:39fundamental kind of basic science.
01:39 --> 01:41Questions for my initial training
01:41 --> 01:44as an undergraduate and graduate
01:44 --> 01:46student and even into my
01:46 --> 01:48postdoc period where one typically
01:48 --> 01:51is defining the kind of areas of
01:51 --> 01:53research that they will pursue,
01:53 --> 01:55and in their independent laboratory.
01:55 --> 01:57But I discovered a connection between
01:57 --> 01:59the cell biology of the nucleus,
01:59 --> 02:02which is something that I had
02:02 --> 02:03been training with
02:03 --> 02:05Gunter Blobel at Rockefeller
02:05 --> 02:07University in Genome Integrity,
02:07 --> 02:09so that is the mechanisms that
02:09 --> 02:11maintain the DNA blueprint
02:11 --> 02:14as it should be and that was
02:14 --> 02:16really just something that I had
02:16 --> 02:18not focused on before
02:18 --> 02:20but it really changed the direction of
02:20 --> 02:23my research and I became very interested
02:23 --> 02:26in how aspects of how a cell works,
02:26 --> 02:28are able to contribute to the mechanisms
02:28 --> 02:30that maintain that genetic code.
02:30 --> 02:32So tell us more about
02:32 --> 02:35that. I think some of us can
02:35 --> 02:37remember back to junior high biology
02:37 --> 02:41where we kind of know what a cell is.
02:41 --> 02:43And we know what a nucleus is and
02:43 --> 02:45housed within that nucleus is the
02:45 --> 02:47DNA which is responsible for that
02:48 --> 02:49genetic blueprint as you say.
02:49 --> 02:52So tell us more about the connection
02:52 --> 02:54that you found between how a cell
02:54 --> 02:56functions and genomic integrity.
02:56 --> 02:57Yeah, so I was
02:57 --> 02:59also fascinated with this
02:59 --> 03:02idea of the the nucleus which
03:02 --> 03:04is the organelle that houses the DNA,
03:04 --> 03:07being kind of the brain.
03:07 --> 03:09Having all of the kind of
03:09 --> 03:11control and that plan
03:11 --> 03:13for the cell, but I think one of the
03:13 --> 03:16things that maybe isn't always captured
03:16 --> 03:19when we kind of make that diorama during
03:19 --> 03:22you know grade school is that actually
03:22 --> 03:25it's not just a big ball of yarn,
03:25 --> 03:28but actually the DNA has lots of different
03:28 --> 03:30regions and these regions are important
03:30 --> 03:32for different aspects of that blueprint.
03:32 --> 03:35And they're not all created equal.
03:35 --> 03:38There are specific regions of the DNA
03:38 --> 03:41that are far more prone to damage.
03:41 --> 03:43And there are also mechanisms to repair
03:43 --> 03:45that damage that may be quite specific,
03:45 --> 03:48so if you have a leak
03:49 --> 03:51in a pipe you may need a plumber, right?
03:51 --> 03:53But if you're siding
03:53 --> 03:54has gone downhill,
03:54 --> 03:57maybe you need someone who is
03:57 --> 03:58more like a Carpenter.
03:58 --> 03:59Or for any
03:59 --> 04:01new paint you're going
04:01 --> 04:04to have a different kind of approach
04:04 --> 04:06depending on what the issue is.
04:06 --> 04:07And it turns out for cells,
04:07 --> 04:08that's similar.
04:08 --> 04:10There are actually different
04:10 --> 04:11DNA repair mechanisms and you
04:11 --> 04:14really need to use the right mechanism
04:14 --> 04:16for the right kind of damage,
04:16 --> 04:19and it turns out that much of that is
04:19 --> 04:21actually dictated by these different
04:21 --> 04:23flavors of the regions of DNA and
04:23 --> 04:25also physically where those different
04:25 --> 04:28regions of the DNA blueprint are
04:28 --> 04:30organized inside the nucleus,
04:30 --> 04:33because it's a much more
04:33 --> 04:34compartmentalized kind of network
04:36 --> 04:39than when we just again think of
04:39 --> 04:42this string that has all of that
04:42 --> 04:43coding material,
04:43 --> 04:44so it's not
04:44 --> 04:47just where the break occurs in the
04:47 --> 04:50DNA or what kind of a break it is,
04:50 --> 04:51whether it's a single strand
04:51 --> 04:54break or a double strand break,
04:54 --> 04:55but where exactly it's
04:55 --> 04:57located within the nucleus.
04:57 --> 05:00We think about two components.
05:00 --> 05:02One exactly as you say physically,
05:02 --> 05:05where is that DNA break in the nucleus?
05:05 --> 05:07And then there's also the
05:07 --> 05:09other attributes of the DNA.
05:09 --> 05:12So DNA doesn't live on its own.
05:12 --> 05:14It's actually wrapped up and packaged
05:14 --> 05:16around proteins that are called
05:16 --> 05:19histones and this packaging is
05:19 --> 05:21really important for whether a
05:21 --> 05:24particular gene may be expressed or not.
05:24 --> 05:26It turns out that a DNA break
05:26 --> 05:29in a region of the genome
05:29 --> 05:31that is coding for a protein,
05:31 --> 05:33so it's going to be transcribed
05:33 --> 05:35into the messenger RNA and then
05:35 --> 05:37translated into a protein.
05:37 --> 05:39Those regions of the genome are
05:39 --> 05:41a bit different than regions of
05:41 --> 05:43the genome that may be silent,
05:43 --> 05:46and so that also just leads to both some
05:46 --> 05:48challenges for DNA repair mechanisms
05:48 --> 05:50and also some activities that
05:50 --> 05:53may actually make it more prone to
05:53 --> 05:54the accumulation of DNA damage.
05:54 --> 05:57And so we think of both
05:57 --> 05:59where the break is
05:59 --> 05:59physically,
05:59 --> 06:02and also where it is in context
06:02 --> 06:04of what else is happening in
06:04 --> 06:06that region of the DNA.
06:06 --> 06:09So we know that DNA can incur various
06:09 --> 06:12forms of damage that can be in coding
06:12 --> 06:14regions or in non coding regions.
06:14 --> 06:17How does that then evolve into
06:17 --> 06:18your research with cancer?
06:18 --> 06:21So initially as I mentioned our
06:21 --> 06:23interest was the idea that these
06:23 --> 06:25different locations in the nucleus
06:25 --> 06:28might be important for making sure that
06:28 --> 06:31those breaks are repaired by the right
06:31 --> 06:34process and in order to study that we
06:34 --> 06:37really need to be able to watch DNA
06:37 --> 06:39repair in a cell that's living while
06:39 --> 06:42it's happening and that as it turns out
06:42 --> 06:44is actually quite a difficult problem,
06:44 --> 06:47and so over the past ten years or so,
06:47 --> 06:50one of the things that my group has
06:50 --> 06:52invested in, is building so called
06:52 --> 06:54assays where we can actually watch
06:54 --> 06:56a single DNA break,
06:56 --> 06:57which we actually control.
06:57 --> 07:00So we induce the break to occur in
07:00 --> 07:03exactly the place where we want it to,
07:03 --> 07:05and then we actually follow the
07:05 --> 07:08repair of that break in real time and
07:08 --> 07:09once we built this system,
07:09 --> 07:12we became very interested in how we might
07:12 --> 07:14leverage it to answer some important
07:14 --> 07:16questions that were really arising
07:16 --> 07:19in the field of cancer treatments.
07:19 --> 07:19And really,
07:19 --> 07:22I was driven towards those questions
07:22 --> 07:24through my interactions with my
07:24 --> 07:26fantastic colleagues here
07:26 --> 07:29at the School of Medicine and at
07:29 --> 07:31Yale Cancer Center who really brought
07:32 --> 07:35a way of connecting the kind of questions
07:35 --> 07:38that I had become interested in,
07:38 --> 07:40again as a postdoc and kind of just
07:40 --> 07:42looking through the microscope
07:42 --> 07:44to where we had a real need to
07:44 --> 07:46understand specific questions in
07:46 --> 07:48the field of DNA repair,
07:48 --> 07:50and particularly those that were
07:50 --> 07:52relevant to the kind of therapies
07:52 --> 07:55that might be used in the context
07:55 --> 07:56where patients have
07:56 --> 07:58defects in DNA repair within their tumors.
07:58 --> 08:00So first question,
08:00 --> 08:02how exactly do you watch DNA being
08:02 --> 08:05repaired in real time?
08:05 --> 08:08I'm kind of blown away by that concept.
08:08 --> 08:10I remember back in junior high
08:10 --> 08:13biology looking down a microscope at
08:13 --> 08:15a cell and looking at the nucleus.
08:16 --> 08:18And sometimes you could even see DNA
08:18 --> 08:21separating into mitotic figures and so on.
08:21 --> 08:24But to actually see DNA being repaired?
08:24 --> 08:27I mean presumably that occurs at a base pair
08:27 --> 08:30level and that's just fascinating to me.
08:30 --> 08:32So how exactly do you do that
08:32 --> 08:35and what kind of magnification
08:35 --> 08:37would you need even to see that?
08:37 --> 08:39Yeah, that's a great question and honestly,
08:39 --> 08:42this is why I'm a cell biologist at the end
08:42 --> 08:45of the day because we love to just look.
08:45 --> 08:48If we have a way we can look at
08:48 --> 08:50something happening in real time that
08:50 --> 08:52is always the best thing in the world.
08:52 --> 08:53However, as you say,
08:53 --> 08:56it's not easy and so our work is built
08:56 --> 08:57on really critical discoveries that
08:57 --> 09:00have driven cell biology, in particular,
09:00 --> 09:01and I'll just tell you about two
09:01 --> 09:03of those that are critical for
09:03 --> 09:05the assays that we've built.
09:05 --> 09:07The first is the advent of
09:07 --> 09:08these fluorescent proteins.
09:08 --> 09:09Green fluorescent proteins
09:09 --> 09:10and red fluorescent proteins.
09:10 --> 09:12Now we have an entire rainbow
09:12 --> 09:14of these fluorescent proteins,
09:14 --> 09:16and so these are proteins that
09:16 --> 09:18fold up and they're able to make
09:18 --> 09:20what's called a chromophore
09:20 --> 09:22and we can actually follow that
09:22 --> 09:24specific molecule in a microscope.
09:24 --> 09:26And what we do is we basically stitch
09:26 --> 09:28that fluorescent protein onto a
09:28 --> 09:30protein that we're interested in,
09:30 --> 09:32and now we can follow our favorite
09:32 --> 09:34protein of interest in a live
09:34 --> 09:36cell on a fluorescence microscope
09:36 --> 09:38that can specifically detect
09:38 --> 09:39that fluorescent protein,
09:39 --> 09:41and so that's one technology
09:41 --> 09:42that's absolutely critical.
09:42 --> 09:43The other,
09:43 --> 09:45and I think this really speaks to
09:45 --> 09:47the importance of kind of basic
09:47 --> 09:49science discoveries and what
09:49 --> 09:52really has impacts on human
09:52 --> 09:54health these days is that we use
09:54 --> 09:56tricks to insert a region that's
09:56 --> 09:58actually taken from a bacteria,
09:58 --> 10:01so it's not native to the cells
10:01 --> 10:02that we are modifying,
10:02 --> 10:05and we essentially take that little sequence,
10:05 --> 10:09and we put it into the place in the genome
10:09 --> 10:10we're interested in and then we
10:10 --> 10:13have a protein that can bind to
10:13 --> 10:15that very specific DNA sequence,
10:15 --> 10:17and so we can monitor any kind of
10:17 --> 10:20region of the genome that we want
10:20 --> 10:22just by doing a little bit of editing
10:22 --> 10:25to that genome and putting these
10:25 --> 10:26in bacterial gene sequences
10:26 --> 10:28into our eukaryotic cell,
10:28 --> 10:30because that's what we want to be studying.
10:30 --> 10:33In terms of the magnification,
10:33 --> 10:34you're absolutely right.
10:34 --> 10:37We are able to do a pretty good
10:37 --> 10:39job following these events
10:39 --> 10:40even with a magnification,
10:40 --> 10:43usually between 100 and 1000 fold over
10:43 --> 10:46what you could see with the naked eye.
10:46 --> 10:49Wow, so essentially you can clip the
10:49 --> 10:52DNA where you want to make a break.
10:52 --> 10:54Insert a bacterial strand of genetic
10:54 --> 10:56material, flag it with a particular
10:56 --> 11:00flag so you know where the break is and
11:00 --> 11:02then have these chromophores which can
11:02 --> 11:05light up when they approach that break.
11:08 --> 11:10That's right, so another critical aspect is
11:10 --> 11:13we have to know a lot about DNA repair,
11:13 --> 11:14and fortunately,
11:14 --> 11:16DNA repair has been a really rich
11:16 --> 11:18area of research for many decades,
11:18 --> 11:20and so building again on the knowledge
11:20 --> 11:22of many others we know pretty well
11:22 --> 11:25about the kind of timing and the events
11:25 --> 11:27that are taking place and repair.
11:27 --> 11:29So protein X shows up,
11:29 --> 11:31and it always shows up before protein Y.
11:31 --> 11:32And as you said,
11:32 --> 11:34we want to know what's happening
11:34 --> 11:36at the base pair level,
11:36 --> 11:38like the smallest unit of DNA.
11:38 --> 11:40We can't really see something
11:40 --> 11:42that small in this assay,
11:42 --> 11:44so we're using proxies of factors
11:44 --> 11:47that we know will show up at different
11:47 --> 11:49points and that allows us to
11:49 --> 11:51essentially monitor distinct events,
11:51 --> 11:53because if we build up our
11:53 --> 11:56library of these different flags that
11:56 --> 11:58indicate different times and repair
11:58 --> 12:01them more able to monitor those events,
12:01 --> 12:03and we're also able to
12:03 --> 12:04monitor them in single,
12:04 --> 12:05individual cells,
12:05 --> 12:08and it's turned out that that's
12:08 --> 12:09really important.
12:09 --> 12:11Because if we look at a million
12:11 --> 12:13cells doing something they all kind
12:13 --> 12:15of do it on a little bit different
12:15 --> 12:18time over a little bit different time,
12:18 --> 12:20then the cell next
12:20 --> 12:21door and so by actually watching
12:21 --> 12:23these events in single cells,
12:23 --> 12:25that really gives us a resolution
12:25 --> 12:26that's really important for
12:26 --> 12:28being able to make very
12:28 --> 12:30mechanistic conclusions from the data.
12:31 --> 12:33So we understand that you've got
12:33 --> 12:36DNA that can get injured and it can
12:36 --> 12:38get injured in a variety of ways
12:38 --> 12:41at a variety of places,
12:41 --> 12:42each of which requires a
12:42 --> 12:44specific mechanism to repair it.
12:44 --> 12:46And we now understand that you've
12:46 --> 12:49built this model to kind of see
12:49 --> 12:50how DNA repairs itself overtime,
12:50 --> 12:53so tell us more about how this gets
12:53 --> 12:55into cancer and into therapeutics
12:55 --> 12:58And we'll have to do that as soon as
12:58 --> 13:01we take a break for a medical minute.
13:01 --> 13:05So please stay tuned to learn more about
13:05 --> 13:08DNA repair and cancer with my guest
13:08 --> 13:08Doctor Megan King.
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13:30 --> 13:32but there is hope,
13:32 --> 13:33thanks to earlier detection,
13:33 --> 13:35noninvasive treatments and the development
13:35 --> 13:38of novel therapies to fight breast cancer.
13:38 --> 13:40Women should schedule a baseline
13:40 --> 13:42mammogram beginning at age 40 or
13:42 --> 13:44earlier if they have risk factors
13:44 --> 13:46associated with the disease.
13:46 --> 13:47With screening, early detection,
13:47 --> 13:49and a healthy lifestyle,
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13:57 --> 14:00as Yale Cancer Center and Smilow
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14:02 --> 14:05new treatments available to patients.
14:05 --> 14:07Digital breast tomosynthesis, or 3D
14:07 --> 14:09mammography is also transforming breast
14:09 --> 14:11cancer screening by significantly
14:11 --> 14:13reducing unnecessary procedures
14:13 --> 14:15while picking up more cancers.
14:15 --> 14:18More information is available at
14:18 --> 14:19yalecancercenter.org. You're listening
14:19 --> 14:21to Connecticut Public Radio.
14:21 --> 14:22Welcome
14:22 --> 14:24back to Yale Cancer Answers.
14:24 --> 14:27This is doctor Anees Chagpar and I'm
14:27 --> 14:30joined tonight by my guest doctor Megan King.
14:30 --> 14:33We're talking about DNA repair and cancer,
14:33 --> 14:35and right before the break we had
14:35 --> 14:38gotten to the point in the story
14:38 --> 14:41where we were talking about the fact
14:41 --> 14:43that DNA gets injured and it can
14:43 --> 14:46get damaged in a variety of places.
14:46 --> 14:49And each of these breaks may be
14:49 --> 14:51specific and may require a specific
14:51 --> 14:54mechanism to repair it and we also
14:54 --> 14:58talked about the fact that Doctor King's
14:58 --> 15:01laboratory had figured out a way to
15:01 --> 15:03actually watch how DNA gets repaired.
15:03 --> 15:06right under a microscope,
15:06 --> 15:07which was just fascinating.
15:07 --> 15:08But now Megan,
15:08 --> 15:10maybe you can help us to understand
15:10 --> 15:12how this really evolves into
15:12 --> 15:14understanding a little bit more
15:14 --> 15:16about cancer and therapeutics.
15:16 --> 15:19We built the capability now of
15:19 --> 15:21monitoring DNA repair and these single cells.
15:21 --> 15:24And now we get to the point
15:24 --> 15:27in a basic scientist life where you
15:27 --> 15:29think about, I've built this assay,
15:29 --> 15:32it took us many years to do it.
15:32 --> 15:35What do we want to study?
15:35 --> 15:38And it's about this time that I had
15:38 --> 15:39been interacting increasingly
15:39 --> 15:42with members of Yale Cancer
15:42 --> 15:44Center and hearing about their
15:44 --> 15:46work in the clinic and their work
15:46 --> 15:48that is more translational.
15:48 --> 15:51So that's when we kind of apply basic
15:51 --> 15:53science and fundamental principles,
15:53 --> 15:55directly to new treatments.
15:55 --> 15:58And through these interactions we became
15:58 --> 16:01very interested in how we might use this
16:01 --> 16:04assay to answer a question that has arisen
16:04 --> 16:06that was clearly critical to the treatment
16:06 --> 16:09of breast and ovarian cancer that is
16:09 --> 16:11tied to this familial cancer susceptibility
16:11 --> 16:14genes BRCA one and 2.
16:14 --> 16:16I allways have a soft spot in my heart
16:16 --> 16:18for BRCA 1 because it
16:18 --> 16:20was discovered by Mary Claire King.
16:20 --> 16:22No relation but we have the same
16:22 --> 16:24initials and last name and in fact
16:24 --> 16:26over the years I've gotten emails
16:26 --> 16:28intended for Mary Claire King.
16:28 --> 16:31So we've struck up already a kind
16:31 --> 16:33of back and forth just because
16:33 --> 16:35of people getting us mixed up.
16:36 --> 16:40And so BRCA one really had
16:40 --> 16:42become a success story of an approach
16:42 --> 16:45to therapy called synthetic lethality.
16:45 --> 16:48And so the idea is that
16:48 --> 16:50BRCA one is very important,
16:50 --> 16:53particularly in a type of DNA repair
16:53 --> 16:55called homologous or combination
16:55 --> 16:58and in individuals who have a
16:58 --> 17:00loss of function and BRCA one,
17:00 --> 17:03this leads to an increased susceptibility
17:03 --> 17:05to breast and ovarian cancer in women.
17:06 --> 17:08And so you are probably quite familiar
17:08 --> 17:10with this because it's become very well known.
17:13 --> 17:15And it's also well known
17:15 --> 17:17even on the scientific front
17:17 --> 17:20because of the advent of a therapy
17:20 --> 17:22which is called PARP inhibitor
17:22 --> 17:23therapies that specifically kill
17:23 --> 17:26tumor cells that are defective in the
17:26 --> 17:29functions of BRCA one or two,
17:29 --> 17:31and actually more broadly in DNA
17:31 --> 17:33repair through this mechanism
17:33 --> 17:34called homologous recombination.
17:34 --> 17:36And so this is fantastic.
17:36 --> 17:39What does that mean for a patient?
17:39 --> 17:41It means that all of their normal
17:41 --> 17:43tissues can tolerate these drugs.
17:43 --> 17:45They really only attack the cells
17:45 --> 17:47that don't have functional DNA repair.
17:47 --> 17:50So DNA repair is this kind of
17:50 --> 17:52double edged sword, on the one hand,
17:52 --> 17:54a defect in DNA repair can lead
17:54 --> 17:56an individual to be vulnerable
17:56 --> 17:58to developing a cancer.
17:58 --> 18:00But if the cancer is defective
18:00 --> 18:01in DNA repair,
18:01 --> 18:03it also opens up a window
18:03 --> 18:05for therapies and PARP
18:05 --> 18:06Inhibitors were something that
18:06 --> 18:09could kind of fit into that window,
18:09 --> 18:11so this was really a very exciting
18:11 --> 18:14time and continues to be a really new
18:14 --> 18:16approach to treating cancers that are
18:16 --> 18:18tied to homologous or combination
18:18 --> 18:21defects which we now know include a
18:21 --> 18:23number of contexts that do not involve
18:23 --> 18:26just BRCA 1 and 2.
18:26 --> 18:26However,
18:26 --> 18:28we also knew quite early on
18:28 --> 18:29that these patients
18:29 --> 18:31would often have acquired
18:31 --> 18:33resistance to the PARP inhibitiors.
18:33 --> 18:35They would initially respond very well,
18:35 --> 18:37but the response would not
18:37 --> 18:39be as durable as they and their
18:39 --> 18:41physicians would like it to be,
18:41 --> 18:43and investigators had gone in to
18:43 --> 18:46try to ask how is it that these
18:46 --> 18:48tumors are evolving, essentially,
18:48 --> 18:50to become resistant to PARP inhibitors,
18:50 --> 18:52and particularly in the case of BRCA 1
18:52 --> 18:54they found that there
18:54 --> 18:56seemed to be secondary loss
18:56 --> 18:59of other repair factors that were
18:59 --> 19:01involved and we became excited
19:01 --> 19:04about the potential of our assay
19:04 --> 19:06to maybe provide some insight
19:06 --> 19:09into how is it that these tumors
19:09 --> 19:11are getting around this therapy,
19:11 --> 19:13and even more importantly,
19:13 --> 19:16might there be ways that we could
19:16 --> 19:18actually target these cells again?
19:18 --> 19:21So kind of re-sensitize them
19:21 --> 19:22to PARP inhibitors,
19:22 --> 19:25and so we modeled these mutations,
19:28 --> 19:31so that cells no longer express a number
19:31 --> 19:34of other factors called 53BP1
19:34 --> 19:37on a complex called shieldin.
19:37 --> 19:39And somehow this allows cells that
19:39 --> 19:41don't have functional BRCA one
19:41 --> 19:44to still survive in the presence
19:44 --> 19:45of PARP inhibitors,
19:45 --> 19:47and so we investigated those using
19:47 --> 19:50this assay and we discovered that the
19:50 --> 19:53loss of these factors that drove
19:54 --> 19:57this PARP inhibitor to no longer work were
19:57 --> 19:59affecting DNA repair in a very
19:59 --> 20:01specific way by unleashing
20:01 --> 20:02a DNA repair factor that really
20:02 --> 20:04shouldn't be functioning and this is
20:04 --> 20:06a protein called the bloom's helicase
20:06 --> 20:09and it was able to kind of step in for
20:09 --> 20:12BRCA one when these other factors
20:12 --> 20:14are silenced and take over and so
20:14 --> 20:17in a sense that seems like a bad thing.
20:17 --> 20:19Some other protein can come in and
20:19 --> 20:21and take the place of BRCA one,
20:21 --> 20:24but it turns out one of the things we
20:24 --> 20:26learned in our experiments was that
20:26 --> 20:29there was kind of a new liability.
20:29 --> 20:31That this activation of this
20:31 --> 20:33bloom's helicase brought along,
20:33 --> 20:35and it's actually now this
20:35 --> 20:37angle that we're targeting,
20:37 --> 20:40with the idea that there will be
20:40 --> 20:42new combination therapies that will
20:42 --> 20:45re sensitize these tumors to PARP
20:45 --> 20:47inhibitors in combination with either
20:47 --> 20:51inhibitors of the bloom helicase itself,
20:51 --> 20:53but also some other additional
20:53 --> 20:56treatments that have already been being
20:56 --> 20:59pushed forward.
20:59 --> 21:01Things like the DNA damage checkpoint,
21:01 --> 21:03which is something that acts
21:03 --> 21:05downstream of unresolved DNA damage,
21:05 --> 21:07so we're pretty excited that these
21:07 --> 21:09kind of very fundamental insights
21:09 --> 21:11from this assay that I've described
21:11 --> 21:14are really leading us to consider
21:14 --> 21:15new combinations of drugs that
21:15 --> 21:17may allow for
21:17 --> 21:20not necessarily to make the PARP inhibitor
21:20 --> 21:23but be a good therapy on its own for longer,
21:23 --> 21:25but how we might use combinations
21:25 --> 21:28that will allow for a very
21:28 --> 21:29durable response for these patients.
21:30 --> 21:33Let me make sure that we've got
21:33 --> 21:35that straight for all of our listeners.
21:35 --> 21:37So normally everybody has functional
21:37 --> 21:41BRCA but when you have a mutation in
21:41 --> 21:43that it no longer becomes effective
21:43 --> 21:47and the function of that BRCA gene is
21:47 --> 21:49really to repair DNA because DNA we
21:49 --> 21:53have in all of our cells and sometimes
21:53 --> 21:56it can just get damaged and BRCA
21:56 --> 21:59actually forms is a very important gene
21:59 --> 22:03that can help us to repair that DNA,
22:03 --> 22:05but when that's defective we get cancers.
22:05 --> 22:08But these PARP inhibitors
22:08 --> 22:11are very effective against tumors
22:11 --> 22:14that have DNA damage that is not
22:14 --> 22:16being repaired by BRCA.
22:16 --> 22:20But then you've got this bloom helicase
22:20 --> 22:24which can step in for BRCA.
22:24 --> 22:27It's almost like a fail
22:27 --> 22:30safe kind of belt and suspenders
22:30 --> 22:33where if one
22:33 --> 22:35repair mechanism doesn't work,
22:35 --> 22:38then another repair mechanism can work,
22:38 --> 22:40but in cancer cells you really
22:40 --> 22:42don't want it to work.
22:42 --> 22:44So what you're now doing is trying
22:44 --> 22:47to find inhibitors to that secondary
22:47 --> 22:49repair mechanism to ensure that the PARP
22:49 --> 22:52inhibitors can kill off those cancer cells.
22:53 --> 22:55Yes, that's exactly right,
22:55 --> 22:58and it had been known for a while that
22:58 --> 23:01there might be these two kind of parallel
23:01 --> 23:03mechanisms to carry out a specific
23:03 --> 23:06step in homologous recombination and
23:06 --> 23:08indeed, it was known already that
23:08 --> 23:09these two mechanisms existed,
23:09 --> 23:11but actually we didn't know very much
23:11 --> 23:14about how a cell could decide to use one
23:14 --> 23:17mechanism that would be this kind of BRCA
23:17 --> 23:18one mechanism which works with
23:20 --> 23:22this blooms' helicase pathway,
23:22 --> 23:24which as you said is kind
23:24 --> 23:25of a backup mechanism.
23:25 --> 23:27One of the things we've discovered is that
23:27 --> 23:30we think that the bloom's helicase mechanism,
23:30 --> 23:31although it's a backup,
23:31 --> 23:33it's really not supposed to
23:33 --> 23:34be working in normal cells,
23:34 --> 23:37and that's why there are a number of factors
23:37 --> 23:39that keep it off and that
23:39 --> 23:41includes these proteins,
23:41 --> 23:43the loss of which can drive
23:43 --> 23:44PARP inhibitor resistance.
23:44 --> 23:46So we think that actually there's
23:46 --> 23:47kind of a gain.
23:47 --> 23:49We would call it a gain of function
23:49 --> 23:51of the bloom's helicase that underlies
23:51 --> 23:53the PARP inhibitor resistance.
23:53 --> 23:56Why might cells not want to be using
23:56 --> 23:58this bloom's helicase all the time?
23:58 --> 24:00We think that it's because actually it's
24:00 --> 24:03not a very well controlled enzyme,
24:03 --> 24:05so its activity in the repair process
24:05 --> 24:08kind of goes wild a bit.
24:08 --> 24:11And even though this allows the cells
24:11 --> 24:13to get around the PARP inhibitor,
24:13 --> 24:15it actually may make them susceptible to
24:16 --> 24:17additional targets
24:17 --> 24:19that are being developed,
24:19 --> 24:21and so we think
24:21 --> 24:23just like a DNA repair defect
24:23 --> 24:25opens up a therapeutic window,
24:25 --> 24:27we think this kind of rewiring from
24:27 --> 24:30BRCA one to the bloom's helicase may
24:30 --> 24:32also open up new ways that we could
24:32 --> 24:34go about treating these tumors.
24:34 --> 24:37So then the next question is,
24:37 --> 24:40is there a way for us to
24:40 --> 24:42figure out either upfront before
24:42 --> 24:44we give any therapy whether a
24:44 --> 24:46particular patient is going to have
24:46 --> 24:48this bloom's helicase turned on or not,
24:48 --> 24:51so that upfront we can decide whether
24:51 --> 24:53we should just give up our PARP inhibitor,
24:53 --> 24:56or whether we need to give dual
24:56 --> 24:58therapy or in a productive manner
24:58 --> 25:00where we can say, well,
25:00 --> 25:02if somebody hasn't responded to the
25:02 --> 25:04PARP inhibitor as we would anticipate,
25:04 --> 25:07is there a way for us to figure out
25:07 --> 25:11if this is the mechanism by which
25:11 --> 25:13the cell is getting around that
25:13 --> 25:14PARP inhibitor and developing resistance
25:14 --> 25:17so that we can add in another drug.
25:17 --> 25:19Do we have those kinds of diagnostics?
25:21 --> 25:22You're absolutely right,
25:22 --> 25:24this is exactly what we would like to have,
25:24 --> 25:26but we don't have it yet,
25:26 --> 25:29so we would like to be able to take a
25:31 --> 25:33tumor sample and ask the question,
25:33 --> 25:36what is happening in this tumor?
25:36 --> 25:38Is this patient likely to
25:38 --> 25:39respond to the PARP inhibitor?
25:39 --> 25:41We know that if they have
25:41 --> 25:43a defect in DNA repair,
25:43 --> 25:44they're likely to respond.
25:44 --> 25:46We know, as I told you, this bloom's
25:46 --> 25:49helicase tends to go kind of overboard,
25:49 --> 25:51and we think that we can design
25:51 --> 25:53what we would call a
25:53 --> 25:54biomarker of that activity,
25:54 --> 25:57because it generates far too much of
25:57 --> 25:58this single stranded DNA generating
25:58 --> 26:00single strand of DNA is a critical
26:00 --> 26:03part of homologous or combination,
26:03 --> 26:03but again,
26:03 --> 26:06bloom's helicase seems to do too much of this,
26:06 --> 26:08and we think that we might be
26:08 --> 26:11able to use proteins that bind
26:11 --> 26:13to that single stranded DNA,
26:13 --> 26:14kind of quantitatively,
26:14 --> 26:16and that may be an indication
26:16 --> 26:18that this is the mechanism by which
26:18 --> 26:20these cells elevated PARP inhibitors.
26:20 --> 26:21Another major mechanism
26:21 --> 26:23of PARP inhibitor resistance
26:23 --> 26:24are so called reversion mutations.
26:24 --> 26:26This is where there's actually a
26:26 --> 26:28second mutation in the BRCA gene,
26:28 --> 26:29which essentially can reconstitute
26:29 --> 26:30its normal function.
26:30 --> 26:31In this case,
26:31 --> 26:33the tumor no longer has
26:33 --> 26:35a DNA repair defect,
26:35 --> 26:36and so we'd really like to
26:36 --> 26:39be able to tell is there a
26:39 --> 26:40reconstitution of normal repair.
26:40 --> 26:42But maybe that repair still has
26:42 --> 26:44some defects that we can target,
26:44 --> 26:46or is repair kind of totally normal,
26:46 --> 26:48in which case we know we're going
26:48 --> 26:50to have to think about another
26:50 --> 26:53type of therapy to treat that patient.
26:53 --> 26:55So these are in development and
26:55 --> 26:57this is something we're really
26:57 --> 26:58interested in,
26:58 --> 27:00particularly again with our
27:00 --> 27:02colleagues here and at Yale Cancer Center.
27:02 --> 27:04To continue to push forward by
27:04 --> 27:06partnering with those clinicians who
27:06 --> 27:08are running clinical trials in this space.
27:08 --> 27:10In patients with BRCA or NOTE Confidence: 0.98452777
27:10 --> 27:11other homologous recombination
27:11 --> 27:13defects who have been enrolled
27:13 --> 27:15on PARP inhibitors and looking at
27:15 --> 27:16those resistance mechanisms.
27:16 --> 27:19And if we can develop these
27:19 --> 27:20types of biomarkers.
27:20 --> 27:23I mean it's so fascinating
27:23 --> 27:25thinking about the fact that
27:25 --> 27:27when we started this conversation,
27:27 --> 27:29we started by saying that you know DNA
27:29 --> 27:33can be damaged in different ways and each
27:33 --> 27:35requires a specific repair mechanism.
27:35 --> 27:38But now thinking about how you're
27:38 --> 27:39actually taking your science
27:39 --> 27:41and in a way kind of again,
27:41 --> 27:43moving towards personalized medicine,
27:43 --> 27:44figuring out, well,
27:44 --> 27:46if somebody develops resistance,
27:46 --> 27:48how exactly is that resistance
27:48 --> 27:49mechanism functioning?
27:49 --> 27:51And how can we get around it?
27:53 --> 27:56Absolutely, and I want to highlight
27:56 --> 27:57we can do this really efficiently
27:57 --> 27:59in cells in a laboratory that's
27:59 --> 28:02never going to tell us about what
28:02 --> 28:04is happening in individual patients.
28:04 --> 28:07So really, this discovery requires the
28:07 --> 28:08commitment of patients who've been
28:08 --> 28:10enrolled on these clinical trials.
28:10 --> 28:12That's not an easy thing to
28:12 --> 28:15ask of patients in this case.
28:15 --> 28:17For example, they've signed up for
28:17 --> 28:19serial biopsies of their tumor,
28:19 --> 28:21but that is absolutely essential
28:21 --> 28:23for us to continue to discover
28:23 --> 28:25the mechanisms that are at play and for
28:25 --> 28:28us to come up with better treatments.
28:28 --> 28:30Doctor Megan King is an associate
28:30 --> 28:33professor of cell biology and of molecular,
28:33 --> 28:34cellular, and developmental biology
28:34 --> 28:37at the Yale School of Medicine.
28:37 --> 28:38If you have questions,
28:38 --> 28:40the address is cancer answers at
28:40 --> 28:42yale.edu and past editions of the
28:42 --> 28:44program are available in audio and
28:44 --> 28:47written form at yalecancercenter.org.
28:47 --> 28:49We hope you'll join us next week to
28:49 --> 28:51learn more about the fight against
28:51 --> 28:53cancer here on Connecticut Public Radio.
28:53 --> 28:55Funding for Yale Cancer
28:55 --> 28:57Answers is provided by Smilow
28:57 --> 29:00Cancer Hospital and AstraZeneca.

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July 11, 2021

Yale Cancer Center

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