Genetic and Environmental Influences in Colon Cancer

Transcript

00:00 --> 00:02Support for Yale Cancer Answers
00:02 --> 00:04comes from AstraZeneca, dedicated
00:05 --> 00:07to advancing options and providing
00:07 --> 00:10hope for people living with cancer.
00:10 --> 00:14More information at astrazeneca-us.com.
00:14 --> 00:16Welcome to Yale Cancer Answers with
00:16 --> 00:18your host doctor Anees Chagpar.
00:18 --> 00:20Yale Cancer Answers features the
00:20 --> 00:23latest information on cancer care by
00:23 --> 00:24welcoming oncologists and specialists
00:24 --> 00:27who are on the forefront of the
00:27 --> 00:28battle to fight cancer. This week,
00:28 --> 00:30it's a conversation about genetic
00:30 --> 00:32and environmental influences in colon
00:32 --> 00:33cancer with Doctor Caroline Johnson.
00:33 --> 00:35Doctor Johnson is assistant professor
00:35 --> 00:38of Epidemiology in the Department of
00:38 --> 00:40Environmental Health Sciences at the
00:40 --> 00:42Yale School of Public Health and Doctor
00:42 --> 00:44Chagpar is a professor of surgical
00:44 --> 00:46oncology at the Yale School of Medicine.
00:48 --> 00:50Caroline you can
00:50 --> 00:52start off by telling us
00:52 --> 00:55a little bit about your research?
00:55 --> 00:58I use a technology called metabolomics
00:58 --> 01:00to investigate specific differences
01:00 --> 01:03in metabolism that affect colon cancer,
01:03 --> 01:05development progression and
01:05 --> 01:07even response to therapeutics.
01:07 --> 01:10So particularly in my research
01:10 --> 01:12I'm interested in examining
01:12 --> 01:15metabolism in patients that develop tumors
01:15 --> 01:18that occur on the right side of the colon,
01:18 --> 01:21so that is the area of the colon between
01:21 --> 01:24the appendix and slightly up from
01:24 --> 01:27there in the rectum and ascending colon,
01:27 --> 01:29because those patients have the poorest
01:29 --> 01:32survival and what we've seen in the
01:32 --> 01:34literature is actually female patients
01:34 --> 01:37have much higher incidence of tumors
01:37 --> 01:40that occur in this region of the colon,
01:40 --> 01:43so we've been using
01:43 --> 01:44metabolomics to get a
01:44 --> 01:46better understanding of the
01:46 --> 01:47metabolism of these tumors.
01:47 --> 01:50So maybe we can stop there
01:50 --> 01:52for a second and just kind of dig a
01:52 --> 01:55little bit deeper into what exactly
01:55 --> 01:58metabolomics is and how that works.
01:59 --> 02:02It's the study of all the small
02:02 --> 02:04molecules that are present within a
02:04 --> 02:07sample so we can take a biological sample
02:07 --> 02:11from a patient such as a blood sample,
02:11 --> 02:14or even a tumor tissue,
02:14 --> 02:17and we can analyze it in an agnostic manner.
02:17 --> 02:19So we examine basically all the different
02:19 --> 02:21levels of all the small molecules
02:21 --> 02:23that might be within that sample
02:27 --> 02:29and this is similar to genomics
02:29 --> 02:30or transcriptomics.
02:30 --> 02:32So small molecules are basically
02:32 --> 02:33metabolites that are within our
02:33 --> 02:35bodies that come from the processing
02:35 --> 02:37of things like dietary products,
02:37 --> 02:39and they produce vital components
02:39 --> 02:41that are needed for our bodies
02:41 --> 02:43for different biological processes,
02:43 --> 02:45such as growth and healing,
02:45 --> 02:47immune responses, energy,
02:47 --> 02:48and even sleep,
02:48 --> 02:51so metabolomic analysis can also
02:51 --> 02:53really show us about the metabolism
02:53 --> 02:56of an individual and it can
02:56 --> 02:58also show us metabolism of things
02:58 --> 03:00like environmental chemicals and
03:00 --> 03:02drugs as well within an individual
03:02 --> 03:04and that could
03:04 --> 03:07be produced by the bacteria or even
03:07 --> 03:09the microbiome within an individual.
03:09 --> 03:11And this technology is particularly
03:11 --> 03:12important for cancer
03:12 --> 03:14because we know that metabolites
03:14 --> 03:17can affect how a tumor grows as tumor
03:17 --> 03:20cells need nutrients and energy and the
03:20 --> 03:22tumors themselves produce metabolites.
03:22 --> 03:23So metabolomics can really provide
03:23 --> 03:26us great insight into how an
03:26 --> 03:27individual produces metabolites
03:27 --> 03:29and how this might propagate
03:29 --> 03:30tumor growth as well.
03:30 --> 03:32So basically you're
03:32 --> 03:34kind of looking at all of these
03:34 --> 03:36metabolites to gain some insight
03:36 --> 03:38into these colon cancers.
03:38 --> 03:40Tell us what sample you used to
03:40 --> 03:42to look at these metabolites.
03:42 --> 03:44One can imagine that there may
03:44 --> 03:47be many options that you would
03:47 --> 03:49have whether it's looking at the stool
03:49 --> 03:52or whether it's looking at tumor tissue,
03:52 --> 03:54or whether it's looking at blood.
03:54 --> 03:58So what exactly do you do to try
03:58 --> 03:59to gain this insight?
03:59 --> 04:02That's a really good question,
04:02 --> 04:05basically we can take anything, we can
04:05 --> 04:07take a blood sample or stool sample,
04:07 --> 04:09or a tumor tissue,
04:09 --> 04:12and we can obtain these from patients,
04:12 --> 04:14and we can extract all the different
04:14 --> 04:17metabolites out of these biological samples.
04:17 --> 04:21And what we end up with is sort of a mixture
04:21 --> 04:24of anywhere from maybe 3000 up to you
04:24 --> 04:27know 10 to 20,000 different molecules
04:27 --> 04:30that could be present within this
04:30 --> 04:33sample within my research so far,
04:33 --> 04:35we have primarily examined
04:35 --> 04:36tumor tissues from patients,
04:36 --> 04:39so with collaborations with
04:39 --> 04:41both Sloan Kettering Cancer Center
04:41 --> 04:43and also Yale Cancer Center,
04:43 --> 04:45we obtained over
04:45 --> 04:47200 tumor tissues from patients
04:47 --> 04:49where these tumors had been obtained
04:49 --> 04:52during surgery and we were able to
04:52 --> 04:55analyze these tissues to examine which
04:55 --> 04:58metabolites were present and how they
04:58 --> 05:00were different between different patients.
05:00 --> 05:02So how they were different between
05:02 --> 05:05both women and men and from patients
05:05 --> 05:08with right sided colorectal cancer
05:08 --> 05:11and also from tumors that occurred in
05:11 --> 05:14other regions of the colon as well?
05:14 --> 05:18And if all of these patients had cancer,
05:18 --> 05:20one would imagine that you're
05:20 --> 05:23really looking at the metabolomic
05:23 --> 05:26profile of tumors in these patients
05:26 --> 05:28is that different than what you
05:28 --> 05:31would expect in normal colon?
05:31 --> 05:33So are there some metabolites
05:33 --> 05:36that you would expect only in
05:36 --> 05:38tumors versus in healthy tissue?
05:38 --> 05:39Yeah, that's
05:39 --> 05:44a great question, so we know that
05:44 --> 05:48tumors have very sort of increased
05:48 --> 05:51rapid growth, so we tend to see metabolites
05:51 --> 05:55linked to energy metabolism and sort of
05:55 --> 05:58making those or encouraging those building
05:58 --> 06:02blocks to be built to build new cells so
06:02 --> 06:05we know there's a lot of what they call
06:05 --> 06:08metabolic rewiring that happens within
06:08 --> 06:12a tumor compared to a normal tissue.
06:12 --> 06:14Andwithin my research,
06:14 --> 06:17we were really interested in looking at the
06:17 --> 06:19tumors themselves and how they differed
06:19 --> 06:22between male and female patients because
06:22 --> 06:24what is quite interesting about
06:24 --> 06:26colorectal cancer and all cancers,
06:26 --> 06:28they tend to have a higher
06:28 --> 06:30incidence in male patients,
06:30 --> 06:32but what we see is that in
06:32 --> 06:34the right side of the colon,
06:34 --> 06:37women tend to have this higher incidence, so
06:37 --> 06:40we wanted to see what was different
06:40 --> 06:42metabolically about these tumors that
06:42 --> 06:45occur specifically in in women with right
06:45 --> 06:47sided colorectal cancer and what we saw
06:47 --> 06:50was that they had this very different
06:50 --> 06:53metabolic profile where they tended to
06:53 --> 06:54generate energy differently
06:54 --> 06:57and they use one metabolites where
06:57 --> 06:59they produce one metabolite school,
06:59 --> 07:01disparaging that seemed to be much
07:01 --> 07:04higher within this set of patients
07:04 --> 07:06than compared to male patients that had
07:06 --> 07:08right sided colon cancer,
07:08 --> 07:11and also patients that had tumors
07:11 --> 07:13in the other side of the colon.
07:13 --> 07:16So we've really gone after this
07:16 --> 07:18metabolic pathway to understand
07:18 --> 07:21more about this side of metabolism and
07:21 --> 07:24potentially how it could in the future
07:24 --> 07:26be potentially targeted for perhaps
07:26 --> 07:29a precision medicine approach for
07:29 --> 07:30these groups of patients.
07:30 --> 07:32That's interesting that
07:32 --> 07:35women have a metabolite that
07:35 --> 07:38processes energy differently than men.
07:39 --> 07:43I just wonder when I think about
07:43 --> 07:46Asparagine I started thinking about
07:48 --> 07:53nucleic acids and amino acids
07:53 --> 07:57that form the building blocks of
07:57 --> 08:01cells and whether these could be
08:01 --> 08:05manipulated based on dietary factors,
08:05 --> 08:06for example.
08:06 --> 08:12So when we think about how cells use energy,
08:12 --> 08:14sometimes that may be
08:14 --> 08:19mediated in part by people's dietary intake,
08:19 --> 08:21did you look at that as a
08:21 --> 08:23potential difference in male
08:23 --> 08:25versus female patients?
08:25 --> 08:27Within our cohort
08:27 --> 08:29we didn't have information on diet,
08:29 --> 08:32but that's very much something that
08:32 --> 08:34would be useful to have something
08:34 --> 08:37like a food frequency questionnaire,
08:37 --> 08:38which is sometimes collected
08:38 --> 08:41for different biobanks
08:41 --> 08:43and in different cohorts.
08:43 --> 08:46Yes, exactly I think it's
08:46 --> 08:48really important here,
08:48 --> 08:52but I think Asparagine does come from
08:52 --> 08:54many many different dietary sources
08:54 --> 08:58and it actually has been seen
08:58 --> 09:00to be produced potentially,
09:00 --> 09:02or metabolize by the microbiome as
09:02 --> 09:05well and it can be produced internally
09:05 --> 09:07through your own biochemical processing
09:07 --> 09:10of other metabolites through an
09:10 --> 09:12enzyme called Asparagine synthetase.
09:12 --> 09:13So, biologically,
09:13 --> 09:16it can come from your internal processing,
09:16 --> 09:19but it can also come from dietary sources,
09:19 --> 09:22and it can come from microbial
09:22 --> 09:23processing as well.
09:23 --> 09:26So, as with many metabolites that
09:26 --> 09:28are present within
09:28 --> 09:31tumors and also present within the colon,
09:31 --> 09:33we always have to take into account
09:33 --> 09:35all these different biological
09:35 --> 09:38sources of where they can come from.
09:38 --> 09:40So we can either
09:40 --> 09:42manipulate them and try and sort of,
09:43 --> 09:44potentially
09:44 --> 09:46reduce the effects of the disease,
09:46 --> 09:47or improve therapeutic response.
09:48 --> 09:49And it seems
09:49 --> 09:50to be so multifactorial when
09:50 --> 09:53you think about where all of
09:53 --> 09:55these metabolites can come from,
09:55 --> 09:57and all of the different processes
09:57 --> 09:59that could be going on
09:59 --> 10:02both within normal cells as
10:02 --> 10:04well as within cancer cells,
10:04 --> 10:06which raises the question,
10:07 --> 10:10do women normally have more of
10:10 --> 10:12this metabolite even outside
10:12 --> 10:13of their colon cancers?
10:14 --> 10:19I think in this context what we've begun to see
10:19 --> 10:22is that Asparagine might be increased in
10:22 --> 10:24these patients because these tumors may be
10:24 --> 10:27what we call nutrient deplete and this is
10:27 --> 10:29something that we still have to look into,
10:29 --> 10:32so we can't really confirm this,
10:32 --> 10:34but just from our metabolomic studies,
10:34 --> 10:36it seems to be indicating this.
10:36 --> 10:38And this is maybe due to differences
10:38 --> 10:40in blood supply to the tumor,
10:40 --> 10:41or something else.
10:41 --> 10:43Less oxygen
10:43 --> 10:46that might be getting to the tumor.
10:46 --> 10:48And when we look at the other
10:48 --> 10:50processes that are going on
10:50 --> 10:53within these samples we see
10:53 --> 10:55that the generation of other energy
10:55 --> 10:58metabolites is different as well,
10:58 --> 11:00which could be indicating that
11:00 --> 11:02there could be something particular
11:02 --> 11:04about how these tumors might be
11:04 --> 11:07growing in this area of the colon.
11:07 --> 11:09So at the moment we don't have normal
11:09 --> 11:12colon tissues from from individuals,
11:12 --> 11:15but that's something that we do want
11:15 --> 11:18to look at to see if
11:18 --> 11:21the patients that do not have
11:21 --> 11:24colon cancer, if the colon tissues have these
11:24 --> 11:27different metabolites that
11:27 --> 11:30could be different between men and women,
11:32 --> 11:35and could affect the development of these tumors.
11:35 --> 11:38You kind of wonder as
11:38 --> 11:41well whether this is cause or effect.
11:41 --> 11:44So in other words, is it that you
11:44 --> 11:48had a tumor which was growing,
11:48 --> 11:50which then caused this
11:50 --> 11:51altered metabolomic profile,
11:51 --> 11:54or was it that you had some other
11:54 --> 11:57processes that were going on that
11:57 --> 11:58altered your metabolomic profile,
11:58 --> 12:01which then spurred on the cancer?
12:01 --> 12:04Did you gain any insight into that question?
12:05 --> 12:09I think it's probably more of the latter.
12:09 --> 12:13We see that Asparagine
12:13 --> 12:15is produced internally.
12:15 --> 12:18As I mentioned through this
12:18 --> 12:19enzyme asparagine synthetase,
12:19 --> 12:23and this enzyme is controlled somewhat by
12:23 --> 12:26another gene mutation of aging mutant Kras,
12:26 --> 12:31so it could be that these tumors
12:31 --> 12:33have this oncogene and it could
12:33 --> 12:36be affecting these metabolites,
12:36 --> 12:39so it could be an effect that we're seeing,
12:39 --> 12:41but it is probably a combination
12:41 --> 12:43of many things, that includes this
12:43 --> 12:45potential mutation to this gene.
12:45 --> 12:48But also it could be the way
12:48 --> 12:50that the tumor is growing
12:50 --> 12:51as I mentioned within the
12:51 --> 12:54colon as well and all together,
12:54 --> 12:56all these different processes are
12:56 --> 12:58causing this effect of this increase
12:58 --> 13:01in Asparagine that seem to help
13:01 --> 13:03propagate the tumor when it
13:03 --> 13:05might be under these stress
13:05 --> 13:08conditions where it's not able to obtain
13:08 --> 13:10nutrients in a normal fashion,
13:10 --> 13:13so I think this is what
13:13 --> 13:14could be happening.
13:14 --> 13:17And also as I mentioned as well,
13:17 --> 13:19this combination of the microbiome
13:19 --> 13:22present as well within the colon
13:22 --> 13:24that could be affecting how this
13:24 --> 13:26metabolite is being processed.
13:29 --> 13:31And it's an interesting puzzle to
13:31 --> 13:33think about how metabolomics works
13:33 --> 13:36along with genetic mutations and so on
13:36 --> 13:38when we think about colon cancer.
13:38 --> 13:40We're going to take a short
13:40 --> 13:43break for a medical minute.
13:43 --> 13:45Please stay tuned to learn more
13:45 --> 13:46about genetic and environmental
13:47 --> 13:48influences in colon cancer with
13:48 --> 13:50my guest Doctor Caroline Johnson.
13:50 --> 13:53Support for Yale Cancer Answers
13:53 --> 13:55comes from AstraZeneca, working to
13:55 --> 13:57eliminate cancer as a cause of death.
13:58 --> 14:01Learn more at astrazeneca-us.com.
14:01 --> 14:03This is a medical minute
14:03 --> 14:05about head and neck cancers,
14:05 --> 14:07although the percentage of oral in
14:07 --> 14:09head and neck cancer patients in
14:09 --> 14:11the United States is only about
14:11 --> 14:135% of all diagnosed cancers,
14:13 --> 14:15there are challenging side effects
14:15 --> 14:17associated with these types
14:17 --> 14:18of cancer and their treatment.
14:18 --> 14:20Clinical trials are currently
14:20 --> 14:22underway to test innovative new
14:22 --> 14:24treatments for head and neck cancers,
14:24 --> 14:26and in many cases less radical
14:26 --> 14:28surgeries are able to preserve nerves,
14:28 --> 14:30arteries and muscles in the neck,
14:30 --> 14:32enabling patients to move,
14:32 --> 14:34speak, breathe and eat normally
14:34 --> 14:35after surgery.
14:35 --> 14:37More information is available
14:37 --> 14:39at yalecancercenter.org.
14:39 --> 14:42You're listening to Connecticut Public Radio.
14:43 --> 14:45Welcome back to Yale cancer answers.
14:45 --> 14:48This is doctor Anees Chagpar and I'm
14:48 --> 14:50joined tonight by my guest doctor
14:50 --> 14:52Caroline Johnson and we're talking about
14:52 --> 14:54genetic and environmental influences in
14:54 --> 14:57colon cancer and right before the break,
14:57 --> 14:59Caroline was telling us about her
14:59 --> 15:01studies looking at metabolomics.
15:01 --> 15:03That is to say the study
15:03 --> 15:04of different metabolites.
15:04 --> 15:06Looking at gender differences
15:06 --> 15:08in right sided colon cancer.
15:08 --> 15:10So Caroline, I wanted to dig into
15:10 --> 15:13that a little bit more because we
15:13 --> 15:16started to talk about whether
15:16 --> 15:18these metabolomic changes
15:18 --> 15:21are what drives the colon cancer or
15:21 --> 15:24whether the colon cancer is what
15:24 --> 15:26drives the metabolomic changes,
15:26 --> 15:30and you had mentioned that the
15:30 --> 15:33metabolomic changes may be in part
15:33 --> 15:35related to mutations in KRas,
15:35 --> 15:39but we know that Kras and oncogenes
15:39 --> 15:43may spur on cancers as well.
15:43 --> 15:46I wonder whether these two processes
15:46 --> 15:48are independent of each other.
15:48 --> 15:50That is to say,
15:50 --> 15:52Kras causes metabolomic changes and
15:52 --> 15:55also causes separately tumor development
15:55 --> 15:58or whether these are Interrelated.
15:58 --> 16:02Do you have any sense on that?
16:03 --> 16:06I think they are interrelated and the
16:06 --> 16:09findings that we have seen
16:09 --> 16:12linking Mutant Kras and Asparagine
16:12 --> 16:15have been seen in other cancers as well.
16:15 --> 16:18So you know the mutant carriers is very
16:18 --> 16:22common in pancreatic cancers and there is a
16:22 --> 16:24clinical trial right now
16:24 --> 16:26actually that I saw yesterday
16:26 --> 16:28for targeting Asparagine by
16:28 --> 16:30using a drug
16:30 --> 16:33along with other first line chemo.
16:36 --> 16:39So we do know that the mutant
16:39 --> 16:41Kras does regulate other
16:41 --> 16:43genes and signaling pathways that
16:43 --> 16:45does affect Asparagine production.
16:45 --> 16:48So I think it's probably a case of mutant
16:48 --> 16:50Kras affecting Asparagine levels.
16:50 --> 16:53But of course, as I mentioned before,
16:53 --> 16:56asparagine can be modulated by other sources,
16:59 --> 17:01and also from the microbiome,
17:01 --> 17:04and we have analyzed the microbiome from some
17:04 --> 17:08of the tumors from the right sided patients.
17:08 --> 17:11So from both men and women,
17:11 --> 17:13and we have a sense that
17:13 --> 17:16there is some microbiota
17:16 --> 17:18that are correlated with asparagine
17:18 --> 17:21levels only in in the female patients.
17:21 --> 17:25So we do believe there is a
17:25 --> 17:27multifactorial effect
17:27 --> 17:28on asparagine production
17:28 --> 17:30that could be itself propagating
17:30 --> 17:33the tumors as well by giving
17:33 --> 17:35them more nutrients,
17:35 --> 17:37we know that Asparagine can increase
17:37 --> 17:41the uptake of other amino acids and can
17:41 --> 17:44affect other processes such as even
17:44 --> 17:45polymetabolite
17:45 --> 17:47production or autophagy,
17:47 --> 17:49another process is like that.
17:49 --> 17:52So I believe this is
17:52 --> 17:54very wide combined effect.
17:54 --> 17:56And really the technology metabolomics
17:56 --> 17:59has allowed us to get an insight into
17:59 --> 18:02this because we can not only
18:02 --> 18:03analyze Asparagine,
18:03 --> 18:06we can analyze all the other
18:06 --> 18:08metabolites that could be
18:08 --> 18:10affected by asparagine levels as well,
18:10 --> 18:12it could be affected by mutant Kras
18:12 --> 18:14so it really is
18:14 --> 18:17a wider scope or a magnifying
18:17 --> 18:21glass really into looking more into
18:21 --> 18:23how these pathways are regulated
18:23 --> 18:25by both genes and metabolites.
18:26 --> 18:28Have you found a difference in
18:28 --> 18:30Asparagine between men and
18:30 --> 18:32women who are Kras negative?
18:32 --> 18:34That is to say, they don't
18:34 --> 18:36have a Kras mutation.
18:36 --> 18:39I wonder whether
18:39 --> 18:41these two are directly linked,
18:41 --> 18:43so for example,
18:43 --> 18:46women may have more Kras mutations,
18:46 --> 18:48and therefore you may be seeing
18:48 --> 18:50these metabolomic differences
18:50 --> 18:52or whether these are really
18:52 --> 18:54separate processes altogether?
18:56 --> 19:01We haven't looked at that specifically
19:04 --> 19:07but what we have done is we've
19:07 --> 19:09looked at survival, and actually
19:09 --> 19:12there's many different
19:12 --> 19:14publicly available data sources
19:14 --> 19:17that we can look at to look at gene
19:17 --> 19:19expression and also patient survival.
19:19 --> 19:21So we looked at mutant Kras
19:21 --> 19:24we looked at asparagine synthetase
19:24 --> 19:27and we saw that patients with these
19:27 --> 19:30genes had much poorer survival if
19:30 --> 19:34they were female and they had a right sided
19:34 --> 19:35tumor so we compared,
19:35 --> 19:37the Kras mutant to the Kras
19:37 --> 19:39wild type, and it was again
19:39 --> 19:41in these different resources
19:41 --> 19:43we saw that it was always the female
19:43 --> 19:44patients of right sided colon
19:44 --> 19:46cancer that had the poorer survival,
19:46 --> 19:48and we looked at asparagine
19:48 --> 19:49levels within our own cohorts.
19:49 --> 19:52And we looked at the survival data because
19:52 --> 19:54our tumors were collected in the 1990s,
19:54 --> 19:56so we were able to follow up
19:56 --> 19:57with survival of the patients.
19:57 --> 20:00And we saw that it was again,
20:00 --> 20:01the women with
20:01 --> 20:03right sided tumors
20:03 --> 20:05that had poor survival,
20:05 --> 20:07and increased risk of recurrence if
20:07 --> 20:09they had high asparagine levels.
20:11 --> 20:13Interesting and did you
20:13 --> 20:15look at whether these asparagine
20:15 --> 20:17levels were higher in tumors that
20:17 --> 20:20were larger versus smaller, or was it
20:20 --> 20:22if you looked at two tumors
20:22 --> 20:24that were identical in terms
20:24 --> 20:26of their size and their grade,
20:26 --> 20:28and the level of invasion
20:28 --> 20:30and their lymph node status,
20:30 --> 20:31and all of the other markers
20:31 --> 20:33that we look at for prognosis
20:33 --> 20:35was asparagine independently
20:35 --> 20:37associated with prognosis?
20:37 --> 20:40We didn't have the size of the tumors
20:40 --> 20:42to sort of understand that,
20:42 --> 20:44but that's a very good question.
20:44 --> 20:46What we did was we we had a very small
20:46 --> 20:49amount of tumor from each patient,
20:49 --> 20:52but it was the same size for each
20:52 --> 20:54patient that the biopsy that we had.
20:54 --> 20:56So we compared between those biopsy sizes.
20:56 --> 20:59But we did take into account things like
20:59 --> 21:02the stage of the patient and we saw
21:02 --> 21:04across the board that it was stage one,
21:04 --> 21:07stage two and three that had
21:07 --> 21:09high levels of asparagine in the
21:09 --> 21:13women with right sided colon cancer,
21:13 --> 21:15but for men they didn't have
21:15 --> 21:17these high levels of asparagine
21:17 --> 21:19at these different stages,
21:19 --> 21:22so it tended to be mostly in the
21:22 --> 21:23women again.
21:23 --> 21:26And so when you looked at prognosis,
21:26 --> 21:28did you look at it and found that
21:28 --> 21:30asparagine was correlated with prognosis?
21:30 --> 21:32Was that independent of
21:32 --> 21:33their stage at presentation?
21:34 --> 21:39Yes, it seems to be
21:39 --> 21:41independent of stages
21:41 --> 21:42asparagine levels within the tumors.
21:42 --> 21:44So what we really want to do
21:44 --> 21:47next is we want to obtain blood
21:47 --> 21:49samples from patients to see if
21:49 --> 21:51we can measure asparagine levels.
21:51 --> 21:53And if this could be potentially a
21:53 --> 21:56biomarker as well for these patients.
21:56 --> 21:57So that's something that we want
21:57 --> 22:00to validate in a larger cohort.
22:00 --> 22:01That's something we're looking into
22:01 --> 22:04right now to collect these samples.
22:05 --> 22:06When we were talking about cause
22:06 --> 22:09versus effect, it really gets to
22:09 --> 22:12your next steps, right?
22:12 --> 22:14So if we think that
22:14 --> 22:16asparagine is really an effect,
22:16 --> 22:20in other words, you have a tumor that
22:20 --> 22:23then causes asparagine levels to go up,
22:23 --> 22:25such that those asparagine levels
22:25 --> 22:27are predictive of prognosis,
22:27 --> 22:28certainly thinking about,
22:28 --> 22:31can we use this as a biomarker,
22:31 --> 22:35especially if it can be found in something
22:35 --> 22:39simple like a blood sample or a stool sample,
22:39 --> 22:40might be helpful.
22:40 --> 22:42On the other hand,
22:42 --> 22:47if we think about it being more of a cause,
22:47 --> 22:48that is to say,
22:48 --> 22:52if you have high levels of asparagine that
22:52 --> 22:54then sets off a cascade that leads
22:54 --> 22:57to worse tumors and worse prognosis,
22:57 --> 22:59then the concept might shift
22:59 --> 23:02not only to be a biomarker,
23:02 --> 23:05but to really think about
23:05 --> 23:06this as a therapeutic target.
23:06 --> 23:11So where where do you kind of come down on
23:11 --> 23:13your next steps with regards to that?
23:14 --> 23:16That's a really good question.
23:16 --> 23:18We are currently designing
23:18 --> 23:21studies to look at the effect of
23:21 --> 23:24asparagine on tumor growth.
23:25 --> 23:27Providing a different cell line,
23:27 --> 23:30and animal models asparagine to see
23:30 --> 23:32if it does propagate tumor growth.
23:32 --> 23:35There was a study
23:35 --> 23:38out in Nature a couple of
23:38 --> 23:40years ago where they in a different
23:40 --> 23:44cancer model, in a breast cancer model,
23:44 --> 23:44they fed mice
23:44 --> 23:46asparagine in their diet and
23:46 --> 23:49they saw that it actually caused
23:49 --> 23:51the primary tumor to metastasize.
23:51 --> 23:53So there's been a number of studies
23:53 --> 23:55that have looked into asparagine and
23:55 --> 23:58have seen that it can propagate tumor growth.
23:58 --> 24:03So we had we have a study that has been
24:03 --> 24:05funded by the American Cancer Society
24:05 --> 24:07where we will be looking at the effect
24:07 --> 24:10of both the gene that produces
24:10 --> 24:12asparagine so asparagine synthetase,
24:12 --> 24:15and we've developed some cell lines where
24:15 --> 24:18we have the knockout of this gene,
24:18 --> 24:22and we will be
24:22 --> 24:24injecting this
24:24 --> 24:28into mice and also to feed them
24:28 --> 24:31asparagine to see if it will actually
24:31 --> 24:34affect tumor growth so
24:34 --> 24:37hopefully in the future
24:37 --> 24:39down the line we can sort of test
24:39 --> 24:42to see if any of the asparagine
24:42 --> 24:44reducing drugs
24:44 --> 24:47could be used as a therapeutic
24:47 --> 24:49to reduce asparagine levels
24:49 --> 24:51in colon cancer patients, potentially.
24:52 --> 24:54iI's so interesting when you talk about that
24:54 --> 24:57study in breast cancer where feeding
24:57 --> 24:59asparagine led to increased metastasis.
24:59 --> 25:02One of the obvious questions I'm sure
25:02 --> 25:05all of our listeners want to know is
25:05 --> 25:10what foods out there are high in asparagine?
25:11 --> 25:13That's something
25:13 --> 25:14we're looking into as well.
25:14 --> 25:17As with any sort of food source,
25:17 --> 25:19there are many different components
25:19 --> 25:21within a
25:21 --> 25:23vegetable or within
25:23 --> 25:26anything that you eat.
25:29 --> 25:32I think if it was going to be given
25:32 --> 25:36as a therapeutic
25:36 --> 25:38I don't know if diet is
25:38 --> 25:41really the best way to approach it.
25:41 --> 25:44It could be better to potentially
25:44 --> 25:45try and reduce
25:45 --> 25:46asparagine levels,
25:46 --> 25:49and that's what I mean as using
25:49 --> 25:52it as a preventative measure
25:52 --> 25:54so encouraging people to eat less
25:54 --> 25:56foods that are high in asparagine.
25:56 --> 25:58Which brings us to the
25:58 --> 26:00question which foods are those?
26:03 --> 26:06At the moment we don't really know
26:06 --> 26:08which foods have high asparagine levels.
26:08 --> 26:10That's something that we
26:10 --> 26:13would need to look into 'cause you know
26:13 --> 26:15each food product does contain many
26:15 --> 26:18different amino acids and other products,
26:18 --> 26:20and it tends to be some food products that
26:20 --> 26:23may have higher asparagine levels have
26:23 --> 26:25other beneficial properties.
26:28 --> 26:29Yeah, that's a
26:29 --> 26:31really interesting point,
26:31 --> 26:33but I think that perhaps
26:33 --> 26:35targeting maybe
26:35 --> 26:37a therapeutic standpoint from
26:37 --> 26:40using something like asparagine.
26:40 --> 26:42AIDS might perhaps be more effective,
26:42 --> 26:45but definitely the diet would be
26:45 --> 26:47something that would be useful
26:47 --> 26:50to look into for these patients.
26:50 --> 26:53Yeah, because they kind of wonder
26:53 --> 26:54whether women just naturally
26:54 --> 26:56gravitate towards eating foods
26:56 --> 26:59that are higher in asparagine
26:59 --> 27:02or whether they process those
27:02 --> 27:06differently such that they end up with
27:06 --> 27:09higher levels of asparagine versus men,
27:09 --> 27:12and so understanding how
27:12 --> 27:15they metabolize those foods
27:15 --> 27:17might play a role, but can you
27:17 --> 27:21comment that in looking at the
27:21 --> 27:23enzymes that breakdown asparagine and
27:23 --> 27:26also those that increase asparagine ,
27:26 --> 27:29did you find a difference between men and
27:29 --> 27:33women in terms of their natural enzymes?
27:33 --> 27:35Even outside of the cancer patient?
27:35 --> 27:37We haven't looked at
27:37 --> 27:39the expression levels of those,
27:39 --> 27:42but that's a really interesting point.
27:42 --> 27:45We do know that the asparagine synthetase
27:45 --> 27:47is associated with poor survival
27:47 --> 27:50if it's a higher expression only in
27:50 --> 27:53women with right sided colorectal cancer.
27:53 --> 27:55But I think also having a
27:55 --> 27:58look more deeply at the microbiome
27:58 --> 28:00because we know that there are many
28:00 --> 28:03species within the microbiome that
28:03 --> 28:05can also metabolize asparagine.
28:05 --> 28:07This could be, you know,
28:07 --> 28:08another therapeutic that
28:08 --> 28:10could be explored as well,
28:10 --> 28:13and I think having a
28:13 --> 28:15more in depth look at
28:15 --> 28:17the microbiome that could be
28:17 --> 28:19present within the stool sample or
28:19 --> 28:21within the tissue samples within
28:21 --> 28:23patients is also really important.
28:25 --> 28:27The other question
28:27 --> 28:29that comes to mind is while your
28:29 --> 28:32research is really focused on the
28:32 --> 28:34differences between men and women,
28:34 --> 28:36one wonders, especially when you
28:36 --> 28:38think about the potential role for
28:38 --> 28:41asparagine in mediating prognosis.
28:41 --> 28:43I'm going back to that study
28:43 --> 28:46that you said was published in Nature
28:46 --> 28:49in the breast cancer model,
28:49 --> 28:51whether if you look at
28:51 --> 28:52men with colon cancers,
28:52 --> 28:54whether men with higher levels
28:54 --> 28:56of asparagine do worse than men
28:56 --> 28:58with lower levels of asparagine
28:58 --> 29:00have you looked at that?
29:00 --> 29:02We have and it doesn't
29:02 --> 29:03seem to be the case,
29:03 --> 29:06so it seems to be sort of what we've
29:06 --> 29:09seen is the opposite way round.
29:09 --> 29:11The with you for male patient
29:11 --> 29:13has higher levels of disparaging.
29:13 --> 29:15They tend to do better.
29:15 --> 29:18So it's really perplexing
29:18 --> 29:19Interesting, you know,
29:19 --> 29:20and it's really fascinating,
29:20 --> 29:21so it's something that you know
29:21 --> 29:23where we're looking into within
29:23 --> 29:24my lab in different models,
29:24 --> 29:26so hopefully we'll get
29:26 --> 29:28better insight into this in the
29:28 --> 29:30the next couple of years or so.
29:31 --> 29:33Doctor Caroline Johnson is assistant
29:33 --> 29:35professor of Epidemiology in the Department
29:35 --> 29:37of Environmental Health Sciences at
29:37 --> 29:39the Yale School of Public Health.
29:39 --> 29:41If you have questions,
29:41 --> 29:42the address is canceranswers@yale.edu
29:42 --> 29:44and past editions of the program
29:44 --> 29:46are available in audio and written
29:46 --> 29:48form at yalecancercenter.org.
29:48 --> 29:51We hope you'll join us next week to
29:51 --> 29:53learn more about the fight against
29:53 --> 29:56cancer here on Connecticut Public Radio.

Information

Genetic and Environmental Influences in Colon Cancer with guest Dr. Caroline Johnson March 21, 2021 Yale Cancer Center visit: http://www.yalecancercenter.org email: canceranswers@yale.edu call: 203-785-4095