New research into the early detection of ovarian cancer

Transcript

00:00 --> 00:03Funding for Yale Cancer Answers is
00:03 --> 00:06provided by Smilow Cancer Hospital.
00:06 --> 00:08Welcome to Yale Cancer Answers
00:08 --> 00:10with Doctor Anees Chagpar.
00:10 --> 00:11Yale Cancer Answers features
00:11 --> 00:13the latest information on cancer
00:13 --> 00:15care by welcoming oncologists and
00:15 --> 00:17specialists who are on the forefront
00:17 --> 00:19of the battle to fight cancer.
00:19 --> 00:21This week it's a conversation about new
00:21 --> 00:24research into the early detection of
00:24 --> 00:26ovarian cancer with Doctor Stacy Malaker.
00:26 --> 00:28Dr. Malaker is an assistant professor
00:28 --> 00:30in the Department of Chemistry
00:30 --> 00:32at Yale University, and Dr.
00:32 --> 00:33Chagpar is a professor of Surgical
00:33 --> 00:36oncology at the Yale School of Medicine.
00:37 --> 00:39So, Stacy, maybe we can start off
00:39 --> 00:41by you telling us a little bit more
00:41 --> 00:42about yourself and what it is you do.
00:43 --> 00:46I got my PhD at the University of Virginia
00:46 --> 00:49where I was in the lab of Professor
00:49 --> 00:53Donald Hunt and he is one of
00:53 --> 00:55the founding fathers of biological mass
00:55 --> 00:57spectrometry and mass spec is kind
00:57 --> 01:00of what I do or what I'm known for.
01:00 --> 01:03And then I did my postdoc in the
01:03 --> 01:06the lab of Carolyn Bertozzi, who just
01:06 --> 01:09recently won the Nobel Prize in Chemistry.
01:09 --> 01:13And there I got really interested in
01:13 --> 01:16a class of of proteins called mucins
01:16 --> 01:19which have tons and tons of sugar
01:19 --> 01:20units on them.
01:20 --> 01:22And so I spent
01:22 --> 01:24five years there researching those.
01:24 --> 01:27And so now in my own laboratory,
01:27 --> 01:30I combine the expertise of the
01:30 --> 01:32instrumentation or the mass spec
01:32 --> 01:35and the sugars or glycobiology
01:35 --> 01:37and we do something
01:37 --> 01:38that's called glycoproteomics,
01:38 --> 01:40which is studying sugars
01:40 --> 01:41that modify proteins.
01:41 --> 01:43So now everybody wants to know, what
01:43 --> 01:46does any of this have to do with cancer?
01:47 --> 01:50Sure. So sugars are altered in
01:50 --> 01:51pretty much every disease that's
01:51 --> 01:54ever been studied and
01:54 --> 01:55primarily in cancer,
01:55 --> 01:57but also other diseases like
01:57 --> 01:59inflammatory bowel disease or cystic
01:59 --> 02:01fibrosis or even heart disease.
02:01 --> 02:04And so we try to monopolize
02:04 --> 02:07on those changes in the sugar
02:07 --> 02:09structures to identify
02:09 --> 02:10new biomarkers or potential
02:10 --> 02:11therapeutics.
02:12 --> 02:15Tell us more about your
02:15 --> 02:18research in particular, what are you
02:18 --> 02:20looking at and how might this make
02:20 --> 02:22a difference to people with cancer?
02:23 --> 02:26Sure, this project in
02:26 --> 02:29particular regarding ovarian cancer,
02:29 --> 02:32right now more than 70% of women
02:32 --> 02:34are diagnosed with ovarian
02:34 --> 02:35cancer in the late stages,
02:35 --> 02:38so stage 3 or stage 4 and the five
02:38 --> 02:40year survival rate for women diagnosed
02:40 --> 02:43in those stages is really poor.
02:43 --> 02:45It's less than 20%.
02:45 --> 02:47Now if ovarian cancer is caught in
02:47 --> 02:49early stages like stage 1 or two,
02:49 --> 02:52that five year survival rate goes up to 95%.
02:52 --> 02:53But the problem is that we don't
02:53 --> 02:55have a really good biomarker
02:55 --> 02:57for ovarian cancer right now.
02:57 --> 03:00Right now what is currently used
03:00 --> 03:02is something that's called CA-125
03:02 --> 03:04and CA-125 happens to be one of
03:04 --> 03:07those mucin type proteins that
03:07 --> 03:09I was talking about earlier.
03:09 --> 03:11And so it's this really,
03:11 --> 03:12really huge protein that's decorated
03:12 --> 03:15by tons and tons and tons of sugars.
03:15 --> 03:18And so 80% of its mass is actually sugar
03:18 --> 03:22units as opposed to the protein backbone.
03:22 --> 03:26Again, the sugar units
03:26 --> 03:29are perpetually disordered in cancer
03:29 --> 03:33yet when doctors are detecting the CA-125,
03:33 --> 03:35they're usually only detecting the
03:35 --> 03:37unmodified regions of the protein.
03:37 --> 03:40And so we want to identify altered
03:40 --> 03:43sugar units on this huge protein
03:43 --> 03:45to ideally detect cancer earlier.
03:45 --> 03:48So that if we can do that and identify
03:48 --> 03:49something that's changed early
03:49 --> 03:51on in the progression of cancer,
03:51 --> 03:54then we could ostensibly develop a
03:54 --> 03:56better biomarker and early stage detection.
03:58 --> 04:01Yeah, I think
04:01 --> 04:03the problem though is
04:03 --> 04:05that for ovarian cancer,
04:05 --> 04:07it's not incredibly common.
04:07 --> 04:09You're quite right, when it is diagnosed,
04:09 --> 04:11it's diagnosed late because we
04:11 --> 04:13don't have a screening test.
04:13 --> 04:16But one of the questions always is,
04:16 --> 04:18you know, are there blood
04:18 --> 04:20tests for detection of cancer?
04:20 --> 04:22Are there blood tests for screening?
04:22 --> 04:25And while CA-125 is a biomarker that
04:25 --> 04:29might be used to help doctors in terms
04:29 --> 04:31of monitoring progression of disease,
04:31 --> 04:34it's really not a widespread
04:34 --> 04:37screening tool like for example,
04:37 --> 04:39a colaguard would be or
04:39 --> 04:40a mammogram would be.
04:40 --> 04:42So is your research trying to look
04:42 --> 04:45at these altered sugar moieties,
04:45 --> 04:47really trying to find a screening modality?
04:47 --> 04:48And if so,
04:48 --> 04:50would that be administered on
04:50 --> 04:52a population basis like to all
04:52 --> 04:55women or would it be for women
04:55 --> 04:57who are particularly at high risk?
04:58 --> 05:00So that's a great question and I
05:00 --> 05:02think that as a basic scientist,
05:02 --> 05:05I can only say that I'm
05:05 --> 05:07hopeful that we'll be able
05:07 --> 05:08to identify something that has
05:08 --> 05:10changed early on in cancer.
05:10 --> 05:13So we're using serum from high risk patients,
05:13 --> 05:17some of whom developed ovarian cancer.
05:17 --> 05:18And so the idea would be that we
05:18 --> 05:20do identify something that could
05:20 --> 05:22be used as a screening modality,
05:22 --> 05:24but I don't want to make any early
05:24 --> 05:26promises since we haven't actually,
05:26 --> 05:27you know, identified anything quite yet.
05:28 --> 05:29Tell us a little bit
05:29 --> 05:30more about your project.
05:30 --> 05:32I mean, when you say you're
05:32 --> 05:34looking at high risk women,
05:34 --> 05:37you tell us more about who those women are.
05:37 --> 05:39And the concept that you kind of laid out,
05:39 --> 05:41if I've understood it correctly,
05:41 --> 05:42is that you're looking
05:42 --> 05:44at these high-risk women.
05:44 --> 05:47You're taking blood samples from
05:47 --> 05:49them and comparing those of them
05:49 --> 05:51who went on to truly develop
05:51 --> 05:54ovarian cancer to those who didn't?
05:54 --> 05:56Is that right?
05:56 --> 05:57That's basically correct.
05:57 --> 06:01So we have access to approximately 4000
06:01 --> 06:04serum samples from high-risk women.
06:04 --> 06:05These are women that have
06:05 --> 06:07been diagnosed with the BRCA,
06:07 --> 06:09one or two mutations.
06:09 --> 06:12So from the point of genetic diagnosis,
06:12 --> 06:15you know throughout the years many,
06:15 --> 06:17many samples have been collected
06:17 --> 06:18from these various women.
06:18 --> 06:21And so to kind of develop our
06:21 --> 06:23technology we're using women that
06:23 --> 06:25have not actually been diagnosed
06:25 --> 06:27just to be able to identify the
06:27 --> 06:29CA-125 modifications or sugar units
06:29 --> 06:32and then we'd basically be given
06:32 --> 06:34a blinded sample and hopefully
06:34 --> 06:36identify those biomarkers
06:36 --> 06:39or what have you that could indicate
06:39 --> 06:42cancer versus non cancerous samples.
06:42 --> 06:46And so that sounds really interesting
06:46 --> 06:49when we think about BRC A1 and two
06:49 --> 06:52often times we think not only of
06:52 --> 06:54ovarian cancer but also of breast
06:54 --> 06:57cancer and one of the questions that
06:57 --> 07:00is often asked is, is there a
07:00 --> 07:03blood test for breast cancer as well.
07:03 --> 07:05You mentioned earlier that the
07:05 --> 07:08sugar moieties tend to be, you know,
07:08 --> 07:10involved or disrupted or altered
07:10 --> 07:12in a variety of processes.
07:12 --> 07:14Do you think that your technology
07:14 --> 07:17might have a role to play in breast
07:17 --> 07:19cancer as well as ovarian cancer?
07:19 --> 07:21Or is it really something specific about
07:21 --> 07:23ovarian cancer that you're looking at?
07:24 --> 07:27It's pretty much any epithelial cancer,
07:27 --> 07:29you know, has these altered
07:29 --> 07:30mucin structures and so
07:30 --> 07:35CA-125 is known as Mucin 16 or Mach 16.
07:35 --> 07:38Mucin one or Mach one is dysregulated or
07:38 --> 07:41upregulated in over 90% of breast carcinomas.
07:41 --> 07:44So this could ostensibly be extended
07:44 --> 07:46to other cancers.
07:46 --> 07:48Pancreatic cancer is another one that
07:48 --> 07:50would be really interesting to look at.
07:50 --> 07:52Pretty much any epithelial cancer is
07:52 --> 07:53associated with dysregulated mucins.
07:54 --> 07:58And so presumably in this population
07:58 --> 08:02of BRCA one and two gene mutation carriers,
08:02 --> 08:05you'd be able to see not only the
08:05 --> 08:07comparison between those who developed
08:07 --> 08:09ovarian cancer and those who did not,
08:09 --> 08:11but also those who developed breast cancer
08:11 --> 08:14or in fact pancreatic cancer because
08:14 --> 08:16that's another cancer that tends to be
08:16 --> 08:18associated with those mutations, right?
08:19 --> 08:21Yeah, absolutely. I would have to talk
08:21 --> 08:23to my collaborators to see how many
08:23 --> 08:25of these women actually did develop
08:25 --> 08:27breast and or pancreatic cancer.
08:27 --> 08:28But that could be done.
08:29 --> 08:32So you know one of the things when we
08:32 --> 08:34think about that kind of an experiment,
08:34 --> 08:35one would think that time
08:35 --> 08:37has something to do with it,
08:37 --> 08:41right that it takes time to develop
08:41 --> 08:43these alterations in the protein
08:43 --> 08:46structure or in the sugar structure
08:46 --> 08:48and it takes time to develop cancer.
08:48 --> 08:53So have you found any correlation
08:53 --> 08:56between the the timing of things,
08:56 --> 08:59I mean presumably if somebody just gets
08:59 --> 09:02a blood sample today and you know
09:02 --> 09:05and then isn't followed for very long,
09:05 --> 09:07you may not find an association.
09:08 --> 09:10Yeah, that's a really great point.
09:10 --> 09:12And you know this is we're very,
09:12 --> 09:14very, very early on in this project.
09:14 --> 09:17It was just awarded a few months ago.
09:17 --> 09:19And so I anticipate we will
09:19 --> 09:21actually see changes over time.
09:21 --> 09:22But because again
09:22 --> 09:24we haven't actually done much
09:24 --> 09:26of the research quite yet,
09:26 --> 09:27I can't give you a straight answer to that.
09:28 --> 09:32But of these 4000 women,
09:32 --> 09:36are you kind of looking at these women
09:36 --> 09:40going forward as well or is this kind of
09:40 --> 09:42a deidentified mass sample that you've
09:42 --> 09:45got where you've got some clinical
09:45 --> 09:48correlation data and would have to
09:48 --> 09:50use covariates to see whether a
09:50 --> 09:52relationship existed. Fo example,
09:52 --> 09:54looking at age as a surrogate.
09:55 --> 09:57OK. So just to clarify,
09:57 --> 09:58it's not 4000 women,
09:58 --> 10:00it's 4000 samples that have been
10:00 --> 10:02collected from I think 50 to 100
10:02 --> 10:05women over the course of their life.
10:07 --> 10:09I see, so then you're comparing samples
10:09 --> 10:10as you go along in time.
10:10 --> 10:14So there might be out of the
10:14 --> 10:174000, say 100 people,
10:17 --> 10:19then that would be like 40 time
10:19 --> 10:21points per person on average,
10:21 --> 10:22something like that.
10:24 --> 10:25So then that's very cool, right,
10:25 --> 10:27because then you could see whether
10:27 --> 10:29these people are
10:29 --> 10:32acquiring these mutations.
10:32 --> 10:35Exactly, exactly.
10:35 --> 10:37So now that makes a lot more
10:37 --> 10:40sense because now you can actually see,
10:40 --> 10:43you know, how long does it take for
10:43 --> 10:45people to develop these alterations and
10:45 --> 10:49do these alterations once they do occur,
10:49 --> 10:53how quickly or not do people develop cancer?
10:53 --> 10:54Is that kind of the idea?
10:54 --> 10:56Yes, precisely.
10:56 --> 10:57Yeah, that's very cool.
10:57 --> 10:59So tell us a little bit more.
10:59 --> 11:01I realized that this is
11:01 --> 11:03a fresh project,
11:03 --> 11:05hot off the presses, just awarded.
11:05 --> 11:07Tell us about some of the research
11:07 --> 11:09that kind of led up to this award.
11:09 --> 11:12What have you found in your
11:12 --> 11:13more earlier studies?
11:15 --> 11:18When I was a post doc,
11:18 --> 11:21when we do mass spectrometry we
11:21 --> 11:24usually take a protein and we digest
11:24 --> 11:26it using enzymes into short peptides
11:26 --> 11:30and then you know we basically blast
11:30 --> 11:32those apart by bombarding them
11:32 --> 11:35with gas molecules and/or radical
11:35 --> 11:37anions and by the way that they
11:37 --> 11:40fall apart we can kind of piece back
11:40 --> 11:42what was present there previously.
11:42 --> 11:43But one of the problems with these really,
11:43 --> 11:45really densely like oscillated proteins
11:45 --> 11:48or you know sugar modified proteins
11:48 --> 11:50is that they can't be chopped up by
11:50 --> 11:52the normal enzymes that we would use.
11:52 --> 11:55And so when I was in my postdoc I
11:55 --> 11:57characterized a series of enzymes that
11:57 --> 12:00we call mucineases that are actually able
12:00 --> 12:02to create short segments of the protein
12:02 --> 12:05that are amenable to mass spec analysis.
12:05 --> 12:07So before we couldn't look at these
12:07 --> 12:10at all by my instrumentation method,
12:10 --> 12:12but now we can actually get pieces and
12:12 --> 12:14see them in the in the mass spectrometer.
12:14 --> 12:17So why is that important?
12:17 --> 12:20Why is looking at these with mass
12:20 --> 12:22spec so important as opposed to
12:22 --> 12:24looking at them with other techniques?
12:24 --> 12:26Or are there no other
12:26 --> 12:27techniques to look at them?
12:28 --> 12:32I mean, you could potentially
12:32 --> 12:36use staining techniques, or NOTE Confidence: 0.93528324
12:36 --> 12:38certain other techniques.
12:38 --> 12:39I'm not saying that mass
12:39 --> 12:40spec is the only technique.
12:40 --> 12:43However, in my opinion,
12:43 --> 12:45and of course I'm biased,
12:45 --> 12:47it's the best way of actually digging
12:47 --> 12:49into what sugar structures are modifying
12:49 --> 12:52what amino acids in what patterns.
12:52 --> 12:54And you're not going to get that molecular
12:54 --> 12:55level of detail using other methods.
12:57 --> 13:00So one of the things
13:00 --> 13:02that you did before embarking on
13:02 --> 13:05this was to figure out how you
13:05 --> 13:07could actually use mass spec to
13:07 --> 13:10look at at these sugar moieties
13:10 --> 13:12in these proteins going forward.
13:12 --> 13:14Precisely, yes. And so my lab,
13:14 --> 13:16you know, I have kind of two arms in
13:16 --> 13:19my laboratory, one being, you know,
13:19 --> 13:21instrumentation development and
13:21 --> 13:24method development so that we can
13:24 --> 13:25better see these altered sugar
13:25 --> 13:27structures and various diseases.
13:27 --> 13:30And then another arm where we study
13:30 --> 13:32the biological role of the altered,
13:32 --> 13:34glycosylation patterns in
13:34 --> 13:35cellular systems.
13:36 --> 13:37Fantastic. Well, we're going to take
13:37 --> 13:40a short break for a medical minute,
13:40 --> 13:41but please stay tuned to learn
13:41 --> 13:43more about the early detection
13:43 --> 13:45of ovarian cancer with my guest,
13:45 --> 13:46Doctor Stacy Malaker.
13:47 --> 13:49Funding for Yale Cancer Answers
13:49 --> 13:51comes from Smilow Cancer Hospital,
13:51 --> 13:53where their Oncodermatology program
13:53 --> 13:55treats dermatologic concerns,
13:55 --> 13:57including very dry skin, itching,
13:57 --> 13:59and skin changes that arise as
13:59 --> 14:01side effects from chemotherapy.
14:01 --> 14:05Smilowcancerhospital.org.
14:05 --> 14:07The American Cancer Society
14:07 --> 14:09estimates that over 200,000 cases
14:09 --> 14:11of Melanoma will be diagnosed
14:11 --> 14:13in the United States this year,
14:13 --> 14:16with over 1000 patients in Connecticut alone.
14:16 --> 14:18While Melanoma accounts for only
14:18 --> 14:21about 1% of skin cancer cases,
14:21 --> 14:24it causes the most skin cancer deaths,
14:24 --> 14:25but when detected early,
14:25 --> 14:28it is easily treated and highly curable.
14:28 --> 14:30Clinical trials are currently
14:30 --> 14:32underway at federally designated
14:32 --> 14:34comprehensive Cancer centers such
14:34 --> 14:36as Yale Cancer Center and Smilow
14:36 --> 14:38Cancer Hospital to test innovative
14:38 --> 14:40new treatments for Melanoma.
14:40 --> 14:42The goal of the Specialized Programs
14:42 --> 14:44of Research Excellence in Skin Cancer
14:44 --> 14:46grant is to better understand the
14:46 --> 14:49biology of skin cancer with a focus
14:49 --> 14:51on discovering targets that will lead
14:51 --> 14:53to improve diagnosis and treatment.
14:53 --> 14:56More information is available
14:56 --> 14:57at yalecancercenter.org.
14:57 --> 14:59You're listening to Connecticut Public Radio.
15:01 --> 15:03Welcome back to Yale Cancer Answers.
15:03 --> 15:05This is Dr. Anees Chagpar,
15:05 --> 15:07and I'm joined tonight by my
15:07 --> 15:09guest doctor Stacy Malaker.
15:09 --> 15:10We're talking about the early
15:10 --> 15:12detection of ovarian cancer.
15:12 --> 15:13As all of you know,
15:13 --> 15:15this has been widely talked
15:15 --> 15:18about as the silent cancer and
15:18 --> 15:20the cancer that whispers.
15:20 --> 15:22And Stacy in her lab is trying to
15:22 --> 15:25figure out whether we can actually,
15:25 --> 15:27well, make ovarian cancer speak
15:27 --> 15:30a little bit more loudly by
15:30 --> 15:32looking at sugar molecules and
15:32 --> 15:35how they're disrupted or altered.
15:35 --> 15:37And Stacy, right before the break,
15:37 --> 15:39one of the things that you were
15:39 --> 15:41talking about is that in the work
15:41 --> 15:44up to your current project which
15:44 --> 15:46is looking at how these alterations
15:46 --> 15:49over time are changing and how that
15:49 --> 15:51might affect people with a BRCA 1 or 2
15:51 --> 15:54mutation both in the
15:54 --> 15:55development of ovarian cancer
15:55 --> 15:57your primary of interest,
15:57 --> 15:58but also other cancers.
15:58 --> 16:01One of the things that your lab
16:01 --> 16:04did was to really look at how
16:04 --> 16:07you can use mass spectrometry
16:07 --> 16:10to look at these alterations,
16:10 --> 16:13which is something that you really
16:13 --> 16:17couldn't do otherwise and you couldn't
16:17 --> 16:20do and look at at the molecular
16:20 --> 16:22level with mass spectrometry.
16:22 --> 16:25So I guess the other question that I have is,
16:26 --> 16:27can you tell us a little bit
16:27 --> 16:29more about this technology?
16:29 --> 16:32I mean presumably if you can now
16:32 --> 16:34look at the sugar moieties and as
16:34 --> 16:37you said before the break that these
16:37 --> 16:40alterations are seen in not just
16:40 --> 16:43cancer but a variety of other diseases.
16:43 --> 16:47How is this being utilized now
16:47 --> 16:50in terms of of looking at other
16:50 --> 16:52cancers and other diseases?
16:52 --> 16:54I mean, how do you see this moving forward?
16:56 --> 16:58Yeah, I mean, the world
16:58 --> 16:59is our oyster really.
16:59 --> 17:01We have this is 1 project of
17:01 --> 17:03of many in my lab right now.
17:03 --> 17:06We're looking at cardiovascular disease.
17:06 --> 17:08We're looking at
17:08 --> 17:09breast cancer,
17:09 --> 17:12but in a different fashion.
17:12 --> 17:14And we also look at changes in
17:14 --> 17:16intestinal linings and stress and
17:16 --> 17:19depression and so on and so forth.
17:19 --> 17:21And so we're really trying to
17:21 --> 17:22monopolize on these developments
17:22 --> 17:24that we've made in order to study
17:24 --> 17:26altered sugar structures in a
17:26 --> 17:28whole host of different diseases.
17:29 --> 17:32And so tell us a little bit more about,
17:32 --> 17:34you know, these sugar moieties.
17:34 --> 17:36I mean, I know that you became very
17:36 --> 17:38interested in these during your postdoc
17:38 --> 17:41working with a Nobel Prize winner
17:41 --> 17:43whose lab really looked at these,
17:43 --> 17:46these molecules. But you know,
17:46 --> 17:49these days I think a lot of people think
17:49 --> 17:52about cancer from the perspective of
17:52 --> 17:56genetics and they think about it from the
17:56 --> 17:59perspective of environmental factors.
17:59 --> 18:01But we really don't think about how
18:01 --> 18:04these two things affect sugars.
18:04 --> 18:06So can you tell us a little bit
18:06 --> 18:08more about those interactions
18:08 --> 18:10and how prevalent they are?
18:10 --> 18:13I mean, do you really think that
18:13 --> 18:15by looking at these sugar muleides
18:15 --> 18:18that we might actually, you know,
18:18 --> 18:21kind of unlock a portion of cancer
18:21 --> 18:23biology that had heretofore been
18:23 --> 18:26largely well overlooked to some degree?
18:28 --> 18:28Yeah, absolutely.
18:28 --> 18:31I think that sugar structures,
18:31 --> 18:33sugar structures, excuse me,
18:33 --> 18:35are extremely difficult to study.
18:35 --> 18:37One of the issues is that
18:37 --> 18:39you just mentioned genetics,
18:39 --> 18:41glycobiology or the sugar
18:41 --> 18:42structures are not templated,
18:42 --> 18:45meaning that there are 200 different
18:45 --> 18:47enzymes that build these sugar
18:47 --> 18:49structures on the surface of our cells.
18:49 --> 18:51And so you can't necessarily
18:51 --> 18:53look at changes in those enzyme
18:53 --> 18:55levels via genetics in order to
18:55 --> 18:57build back up what's possibly
18:57 --> 19:00going to be on the cell surface.
19:00 --> 19:01And so because of that it's
19:02 --> 19:04much more difficult to study and
19:04 --> 19:07so it's lagged behind in you know,
19:07 --> 19:11in comparison to more general fields like
19:11 --> 19:14genomics or transcriptomics or proteomics.
19:14 --> 19:15And so
19:15 --> 19:17we really want to monopolize on these
19:17 --> 19:19changes in order to break open a
19:19 --> 19:21whole new area of cancer biology.
19:22 --> 19:25I mean, do you think that there's an
19:25 --> 19:28interplay between genomics and
19:28 --> 19:30these sugar structures?
19:30 --> 19:33Or do you think that these are two
19:33 --> 19:35separate issues that they cause or
19:35 --> 19:38are affected by cancer independently?
19:38 --> 19:38In other words, I mean,
19:38 --> 19:40do you think that these two
19:40 --> 19:41play together or not really?
19:42 --> 19:43Oh, they definitely do.
19:43 --> 19:45It's just that you can't look at enzyme
19:45 --> 19:47changes and then immediately know how
19:47 --> 19:49that's going to change the sugar
19:49 --> 19:52structures on the outside of the cell.
19:52 --> 19:55But you can kind of gain hypothesis by
19:55 --> 19:57looking at changes in the enzyme levels.
19:57 --> 20:00So if for instance,
20:00 --> 20:02there's a capping structure called
20:02 --> 20:04sialic acid and you can look at the sial
20:04 --> 20:06transferases and if those are up or down
20:06 --> 20:08you could then gather that your
20:08 --> 20:10structures will have more or less of a
20:10 --> 20:12certain type of of that sugar structure,
20:12 --> 20:14but it won't tell you exactly
20:14 --> 20:15what it's modifying.
20:15 --> 20:16So what protein it's on or
20:16 --> 20:18it won't tell you exactly what
20:18 --> 20:20type of sugar structure it's
20:20 --> 20:22on and so on and so forth.
20:22 --> 20:25And so going back to
20:25 --> 20:27the project for which you were just
20:27 --> 20:29awarded a grant where you're looking
20:29 --> 20:32at these BRCA mutation carriers,
20:32 --> 20:36is it possible that BRCA in and of itself,
20:36 --> 20:41I mean we know BRCA as being a gene which
20:41 --> 20:44is largely responsible for DNA repair.
20:44 --> 20:47And so when you get a mutation in that,
20:47 --> 20:50it's difficult to correct those
20:50 --> 20:52mistakes that your DNA may have and
20:52 --> 20:54the thinking is that
20:54 --> 20:57really leads to the higher risk of
20:57 --> 20:59developing a variety of malignancies.
20:59 --> 21:03So if genetics and these altered
21:03 --> 21:05sugar structures are related,
21:05 --> 21:08do you think that
21:08 --> 21:10BRCA might be doing something to the sugar
21:10 --> 21:13structures and are you looking at that?
21:13 --> 21:14For example,
21:14 --> 21:17are you comparing BRCA carriers to
21:17 --> 21:20people who are not BRCA carriers
21:20 --> 21:22and seeing whether there's a
21:22 --> 21:23difference in terms of
21:23 --> 21:25these sugar structures between
21:25 --> 21:26these two populations?
21:27 --> 21:29That's not something that we're currently
21:29 --> 21:31looking at simply because we
21:31 --> 21:34only have access to these BRCA1 and 2 samples.
21:37 --> 21:40But we could ostensibly look at healthy,
21:40 --> 21:42you know, healthy samples or healthy
21:42 --> 21:44patient serum in order to compare them.
21:44 --> 21:45So definitely something we could do,
21:45 --> 21:46but not something that's
21:46 --> 21:49currently on our docket.
21:49 --> 21:51And then the other thing that I
21:51 --> 21:53kind of wonder about is one of the
21:53 --> 21:54questions I always get asked is,
21:54 --> 21:57well, why did I get cancer?
21:57 --> 22:00Can you tell us a little bit more
22:00 --> 22:02about whether you think that
22:02 --> 22:04having these altered sugar moides
22:04 --> 22:06might have something to do with
22:06 --> 22:09people's risk of developing cancer?
22:09 --> 22:10And secondary to that,
22:10 --> 22:13why do people have these alterations
22:13 --> 22:15in these sugar moides anyways?
22:15 --> 22:17I mean what causes that?
22:17 --> 22:19Again, that's a very,
22:19 --> 22:21very loaded question.
22:21 --> 22:22So what was the first part
22:22 --> 22:23of the question?
22:23 --> 22:26Could these altered sugar Moides
22:26 --> 22:28be part of the explanation of why
22:28 --> 22:30some people develop cancer even
22:30 --> 22:32though they did everything right?
22:33 --> 22:36Sure. So I mean there are many,
22:36 --> 22:38many possible answers to that question,
22:38 --> 22:40but I'll probably lean into the
22:40 --> 22:41one that I'm most familiar with.
22:41 --> 22:43So you know, cancer immunotherapies
22:43 --> 22:46are the the new pillar of
22:46 --> 22:48treatment as I'm sure you're aware.
22:48 --> 22:50And so altered sugar structures
22:50 --> 22:52are a way that cancer cells can
22:52 --> 22:54actually avoid the immune system and
22:54 --> 22:57the immune system is really key in
22:57 --> 22:59getting rid of cells that have become
22:59 --> 23:02transformed or cancerous.
23:02 --> 23:04And so there's this really fine-tuned
23:04 --> 23:06balance there where you want your
23:06 --> 23:08immune system to be active and
23:08 --> 23:09killing off these cancer cells.
23:09 --> 23:11Now the sugar moieties can actually
23:11 --> 23:14act as a mechanism to shield the
23:14 --> 23:16cancer cell from immune cells
23:16 --> 23:18that would normally kill it off.
23:18 --> 23:19For instance,
23:19 --> 23:22my lab studies what's called a checkpoint
23:22 --> 23:24inhibitor where when that
23:24 --> 23:27checkpoint inhibitor is bound to one
23:27 --> 23:29of its ligands through sugar structures,
23:29 --> 23:31it shuts down T cell function.
23:31 --> 23:35And it's so important that antibodies
23:35 --> 23:37that block that interaction are currently
23:37 --> 23:39being investigated in the clinic.
23:39 --> 23:41And so we're trying to again monopolize
23:41 --> 23:43on the altered sugar structures
23:43 --> 23:45in order to potentially develop
23:45 --> 23:47a better cancer immunotherapy.
23:47 --> 23:49But basically kind of summarizing that
23:49 --> 23:51is that these sugar moieties can serve
23:51 --> 23:53to shut down various types of immune
23:53 --> 23:56cells which then allow the tumor cells
23:56 --> 23:58to proliferate and become
23:58 --> 24:01a solid tumor or various cancers.
24:02 --> 24:06So why do some people get these
24:06 --> 24:08altered sugar moieties that can
24:08 --> 24:11essentially shut down your immune
24:11 --> 24:13system or at least its ability to
24:13 --> 24:16detect cancer and other people don't?
24:16 --> 24:19I mean, are there factors that drive that?
24:19 --> 24:21You know, some people might be wondering,
24:21 --> 24:22is it the sugar that I'm eating
24:22 --> 24:24or is it how I metabolize it?
24:25 --> 24:26Or is it, you know, diabetes?
24:26 --> 24:30Or is it something to do with my genetics?
24:31 --> 24:32Yeah. So I mean that's a great question
24:32 --> 24:33that I don't have the answer for.
24:33 --> 24:35I will specify that the
24:35 --> 24:37sugars that you're eating are very,
24:37 --> 24:38very, very different than the
24:38 --> 24:40sugars I'm talking about.
24:40 --> 24:42I mean, essentially they can get
24:42 --> 24:44metabolized and turned into the sugar
24:44 --> 24:46structures that are on the cell surface.
24:46 --> 24:47But I'm not looking at glucose
24:47 --> 24:49or sucrose or anything like that.
24:49 --> 24:51These are very different structures.
24:52 --> 24:53And so, you know,
24:53 --> 24:56I think a lot of people may be asking,
24:56 --> 25:00especially now that the WHO is
25:00 --> 25:02coming out with their statement
25:02 --> 25:05against some artificial sweeteners of
25:05 --> 25:08thinking that they may be carcinogenic.
25:08 --> 25:11Do do those have anything to do with the
25:11 --> 25:15sugar moieties that you're talking about?
25:15 --> 25:18I don't know, my understanding
25:18 --> 25:20for those those altered
25:20 --> 25:22sugar moieties that are in,
25:22 --> 25:23you know artificial sweeteners and
25:23 --> 25:25so on is that they can't be broken
25:25 --> 25:27down or metabolized in the same
25:27 --> 25:28way that normal sugars would be.
25:28 --> 25:31But that is just what I understand.
25:31 --> 25:34I have not studied up on that too much.
25:35 --> 25:39So for the alterations
25:39 --> 25:42of sugar moties, I mean the
25:42 --> 25:44the truth of the matter is,
25:44 --> 25:46that at least the research
25:46 --> 25:47that you've done so far,
25:47 --> 25:52your hypothesis is that these alterations
25:52 --> 25:54have a role to play in cancer,
25:54 --> 25:57whether it's the immune system
25:57 --> 26:00evading cancers or you know,
26:00 --> 26:03increasing risk or whatever.
26:03 --> 26:05Do we know of any risk factors
26:05 --> 26:07that make people more susceptible
26:07 --> 26:09to having altered sugar moieties,
26:09 --> 26:10the ones that you're studying?
26:12 --> 26:15I mean not that I'm aware of.
26:15 --> 26:17I think that if you did
26:17 --> 26:17genetic studies again,
26:17 --> 26:20you could probably create hypothesis
26:20 --> 26:22and individuals regarding different
26:22 --> 26:24enzymes that are up or down regulated.
26:24 --> 26:26But as far as I'm aware,
26:26 --> 26:29there's not anything like a
26:29 --> 26:30BRCA1 that would definitely
26:30 --> 26:32indicate that you're going to have
26:32 --> 26:33these altered sugar structures.
26:34 --> 26:37And my perception is from your
26:37 --> 26:40description of your earlier study,
26:40 --> 26:42is that it's not like you're born
26:42 --> 26:44with these altered sugar moieties,
26:44 --> 26:46it's that they develop over time.
26:46 --> 26:47Is that right?
26:47 --> 26:49I mean it would be kind of similar to,
26:49 --> 26:52you know, genetic mutations that
26:52 --> 26:55accumulate over time in cancer cells.
26:55 --> 26:57And again,
26:57 --> 26:59you were asking if genetics and
26:59 --> 27:00altered sugar structures are related.
27:00 --> 27:02If you acquire many,
27:02 --> 27:05many genetic mutations over time,
27:05 --> 27:07you tend to develop cancer.
27:07 --> 27:09Similarly, you would also
27:09 --> 27:11mutate these various glycan structures
27:11 --> 27:14on the surface of cells.
27:15 --> 27:18And so it sounds like there's a lot
27:18 --> 27:20going on in your laboratory both
27:20 --> 27:23on the kind of developing the
27:23 --> 27:26methodologies as well as in terms of
27:26 --> 27:28looking at the actual clinical impact
27:28 --> 27:30of these altered sugar moieties.
27:30 --> 27:33Looking forward, what projects are you
27:33 --> 27:35most excited about and what do you
27:35 --> 27:38think we can expect to hear about in
27:38 --> 27:40the next year or two or five or 10?
27:42 --> 27:45Oh gosh, my students listen to this and
27:45 --> 27:46I won't say their individual projects.
27:46 --> 27:48I don't want to pick favorites.
27:48 --> 27:50Obviously I'm very excited about
27:50 --> 27:52this ovarian cancer project simply
27:52 --> 27:54because I think that, you know,
27:54 --> 27:56CA-125 is really a black box of information
27:57 --> 27:59that I think we can monopolize on to
27:59 --> 28:01develop an improved diagnostic tool.
28:01 --> 28:03And it's a somewhat selfish project
28:03 --> 28:07because I am a BRCA 2 carrier.
28:07 --> 28:09So I would like to identify ovarian
28:09 --> 28:12cancer earlier for my own self
28:12 --> 28:14and family in in addition to all
28:14 --> 28:17of the women that are at risk.
28:17 --> 28:19But I also, you know,
28:19 --> 28:21I love all of my projects equally in my lab,
28:21 --> 28:23and I'm really excited about the
28:23 --> 28:25instrumentation developments that we have,
28:25 --> 28:27as well as really cracking open
28:27 --> 28:30all of the biological underlying
28:30 --> 28:31of altered glycosylation.
28:32 --> 28:34Doctor Stacy Malaker is an assistant
28:34 --> 28:36professor in the Department of
28:36 --> 28:38Chemistry at Yale University.
28:38 --> 28:40If you have questions, the address
28:40 --> 28:42is Cancer Answers at Yale dot Edu.
28:42 --> 28:45And past editions of the program
28:45 --> 28:47are available in audio and written
28:47 --> 28:48form at yalecancercenter.org.
28:48 --> 28:51We hope you'll join us next week to
28:51 --> 28:53learn more about the fight against
28:53 --> 28:55cancer here on Connecticut Public Radio.
28:55 --> 28:57Funding for Yale Cancer Answers is
28:57 --> 29:00provided by Smilow Cancer Hospital.

Information

New research into the early detection of ovarian cancer with guest Dr. Stacy Malaker July 30, 2023 Yale Cancer Center visit: http://www.yalecancercenter.org email: canceranswers@yale.edu call: 203-785-4095