26th Annual Biomedical Distinguished Lecture – Jonathan Brody

ladies and gentlemen are you ready
forever it is with great honor and privilege I introduce to you our 26th
annual distinguished speaker there is Sun Davis professor of surgery
pathology anatomy and cell biology from Sidney Kimmel please join me to give a
warm welcome to dr. Jonathan Berg Wow glad I hope that was recorded
because I can just bring that into my annual review you know or show it to my
wife when she gets upset with me that it I didn’t change our kid’s diaper or
something but I am doing something but thank you very much I mean this has been
a wonderful afternoon visiting with some folks and and just the energy in this
community here is is really palpable I wonder I was sort of thinking here in
these introductions and being out here because I’m usually in the in the lab or
thinking about grants I wonder it’s the first easy question you know want to
engage the students everyone how many here feel lucky to be here and and I’m
not talking about listening to me I’m talking about being on campus here so if
and it’s okay if you didn’t raise your hand but I being here reminds me of my
days of being in a small school and I think then if someone asked me that
question I actually may not have raised my hand to be honest with you to make
you realize but now I appreciate how much this type of education is and I and
and your relationships with your faculty such as you know Lakshmi and others
around is amazing I think it’s it’s incredible experience to engage with
these incredibly delightful intellectual beautiful people and so take advantage
of that if I can come here if you don’t learn about pancreatic cancer or DNA or
anything else that there’s one thing you take away from the lecture appreciate
what you have right here right now because when you get out in the in the
real world which you’ve probably heard it’s amazing if you you know follow your
bliss and all that but to sit here and think and be amongst intellectuals and
do that in a way that you know is is something in the society
that usually people don’t really people take for granted really take advantage
of that so that’s my opening line here so I have a few disclosures about
funding sources and other things and the main thing I wanted to say which I think
was important I’ll get back to which is what Lakshmi talked about was I did I
went to college on a music scholarship so again I’m trying to relate to the
students in the room who might think like okay well this guy’s published X
the amount of publications he’s you know spent years in school training other
things again when I was sitting there I was dreams of being a drummer and
quickly when I learned coming from a small little town in Maryland and going
up to New York with my music scholarship I realized quickly that trying to make a
living out as a drummer was going to be a little bit difficult the competition
was tough and I learned two seconds about this that I learned that I found
it really interesting but I unfortunately I wanted to make a living
and I wanted to do something that would have some longevity I actually really
believe it or not love playing basketball even though I’m sort of
height challenged here that wasn’t gonna happen that didn’t even happen on my JV
team so I learned quickly that you know there’s other ways to find what you love
and I learned that for me science was learning my scales if you
will in music and then trying to be creative with it and to me it’s the
greatest life I know because there’s two things that are involved with it in
relation to your college here is it’s about education and discovery and so I
get to do education every day and I get to discover things and study things that
no one else does in the world and to me that’s a you know to me that it’s an
amazing life and I’m grateful every day so I’m going to talk a little bit at
cancer I’m gonna go in and out of it if I get too dense with stuff I’m gonna
actually and go through the slides I would love
it seems like everyone right now I is really engaged which is great and were
like to keep that engagement I’d love to make it a dialogue by the end of the
lecture so so I’ll try to get through some concepts of my some ideas that are
a little bit different a little bit out of the box if you will about the way we
view about cancer and why pancreatic cancer is so bad so initially people I
think I put the slide up here because when people think about cancer and how
many people either knew someone a friend a loved one who either was touched
yourself or you know a family member who’s touched by cancer okay so yeah so
you know you’re you’re talking about a disease that depending on the statistics
one in three or one and four we’re gonna know someone and we’re all you’re very
young but we’re all old enough that we know either our parents know someone etc
and it is it is a disease of age and I’ll get into that a little bit but I
think when we think about cancer when students think about cancer we think
about it in this sort of lush setting and one of the things that makes
pancreatic cancer really unique in fact is that this is the way pancreatic
cancer is it’s in a desert it grows in a desert it develops in a desert and why
does that make that difficult I’ll let you stop and think about this for a
second because you can imagine that these lush trees if they get into a
harsh setting they’re not going to survive however if you move this around
the country or around the world into different harsh settings this is going
to survive and grow and so what pancreatic cancer does as it develops
over time and it takes about 10 or 20 years to develop it develops in a very
harsh setting and because of that it can survive a lot of different assaults
including therapies and chemo therapies and and targeted agents so this this can
grow and this is really I think one of the main reasons why pancreatic cancer
is so robust and able to grow in different settings and what we talked
about metastasize go from a primary site and go live in another neighborhood if
you another organ so it can go outside the
pancreas and live either in the liver or the lung and other places and that’s
because it grows up in a very harsh environment
another reason is for pancreatic cancer this comes from a from a review that we
wrote we had an artist come in and they wanted to draw a picture of pancreatic
cancer and me and my colleague Michael Fishbein
we explain this to the artist and the artist drew this picture which is really
brilliant these are the tumor cells these are all the different cells that
are within a pancreatic cancer so when dr. Yeoh resect a pancreatic tumor only
about 30 percent of those cells are truly tumor cells the rest of them are
these elements of these micro environment these different fibroblast
immune cells different stellate cells these are just names of different cells
that are not tumor cells that actually are built into the tumor and that that
could be for a whole other two-hour lecture I’m gonna go on here and
continue with my philosophy of what goes on with with cancer in general and how
we as a research community views it so there’s a little bit of a complicated
slide but bear with me here this is at the point in which we recognize that
there is a tumor so in this case a pancreatic tumor this is years below
here on the x-axis so you can see that minus 20 years is when the initiation of
the tumor happens and this is one of the reasons why pancreatic cancer in many
cancers our disease of people of their 6th and 7th and 8th decades of life is
because this initiation happens so early on
typically this starts maybe with some environmental clues but it happens with
a specific mutation in a gene called K wrasse don’t need to know that but K
wrasses a mutation that you might have heard about that really initiates a lot
of different cancers not just pancreatic cancer but lung cancer and summonses
colon cancer and you have this initiation event that happens and I’m
gonna get into actually one of your for more distinguished lecturers actually
paved the way for this idea I’m going to talk about that in a minute
but this initiation actually starts the development of cancer and over time
mutations are gained and the right amount of mutations are grained that you
actually get cancer that gets detected presents itself in the patient and
pancreatic cancer it might be jaundice they might have back pain they might
have a sudden unintended weight loss they might lose 1015 pounds and the
doctor says well it’s great have you been exercising no that’s a big that’s a
big clue and in fact we’re trying to find ways in which to monitor that on an
app so we can detect people earlier but what happens here is that the cancer is
detected and then we start treating the cancer and so based on this finally you
can see that what we do is we start treating the cancer but then the
survival the fittest those cells that are able to grow in the desert can
actually live longer and they go on and it kills the patient so this is the
current I would say overview paradigm that a lot of whether your cancer
geneticist whether you’re studying transcription whether you’re studying
cell biology this is an overview of how I think the world views it so what about
the patient so we have this amazing patient
symposium I you’re all welcome to come you can just contact me it’s every
November this past year was November 10th and this is some people believe
this is the largest group of survivors of pancreatic cancer in a building in
the country and that’s all because of dr. Yeoh so we have over 300 people that
come and you know it’s soon to become the second leading cause of
cancer-related deaths the five-year survival rate on pancreatic cancer if
you get diagnosed all comers all stages as 9% so just imagine that these
patients basically were told and they you know unfortunately nowadays you can
just do a google search you find out your aunt gets pancreatic cancer your
mom your dad calls you and says you know you’re smart you’re at chestnut health
and you just google it and you say oh my they have a nine percent chance of
living five years and if you’re treatable with surgery you only had that
only goes up to about twenty to twenty five percent so the best chance of a
cure is for surgery now this is a woman Margaret crook who back in 2007 dr. Yeoh
just to give you a side story dr. Yeoh told me about Miss crook and I’m allowed
to talk about her because she’s consented so there’s no HIPAA violation
and she posts on Facebook believe it or not her story but she was diagnosed with
pancreatic cancer but she also had other cancers and it turns out that she had
family members who had cancer and so dr. Yeoh consulted me about it and I said
you know let’s sequence her tumor and it turns out she had a specific gene
mutation in a gene called bracha – that was probably linked to why she had other
cancers and why her family members had cancer and because of that we put her on
a specific cocktail of drug an agent that specifically targets that and I’ll
talk a little bit about it anywhere anyway this is she had a nine percent
chance to live five years that was in 2007 this is her in 2018 she comes to
the symposium every year when I give my talk I make her stand up and I embarrass
her it’s my favorite part of the year and you know she had surgery done by dr.
go and she’s she’s a lovely woman so the question is why can’t we get more
examples like like Margaret quick what is really happening out there so a very
talented surgical oncologist Jordan winter and dr. Abbey nefler who is a
surgeon from Israel who’s now in my was in my lab and now he’s back in my lab he
asked the question to these patients what do you view what is a cure because
we can sit around as academics and sort of say well what we think is a cure you
know is if if it’s easy for us to say that if a patient was diagnosed if Alex
Trebek lives five years this is a success story but if you’re
Alex Trebek you’re Alex Trebek’s wife or child five years really isn’t great
imagine if you were told today that you have five years to live I think you
might live your life a little bit differently even you might get up and
leave this lecture but the reality is is that this is not a great number right
and we wanted to ask the question what did these patients and their caregivers
what do they think Acuras let’s ask them they’re the ones who are truly affected
by it were the academics sitting in our ivory towers so what they said is you
know what a cure for me is that the person next to me who’s the same age as
me my friend that I live as long as them who’s not diagnosed so we’re talking
pretty good expectation and I and I would say to all of us we all expect to
live as long as our you know our age-related partner so III think that
that’s a reasonable request so we ask the question we went into a large seer
database and we asked the question let’s let’s let’s ask people who are diagnosed
at either 65 or 70 what is their normal lifespan past the time that they’re you
know at the time they’re 65 you know some of them they live 13 15 years later
and how is that compared to let’s give the best-case scenario the pancreatic
cancer patients that do get surgery put on them so there’s four stages in cancer
the fourth stage is the worst the first stage is the best diagnosis so these are
stage one by definition pancreatic cancers it turns out that only one to
two percent of these people who have the best treatment option actually meet that
criteria so by definition by the patients and their families we are only
reaching a cure one to two percent of the time so that if that’s not to me
more than showing statistics and other things to me that’s very sobering that’s
where we’re at with pancreatic cancer and that’s why it’s one of the most
deadly diseases out there so there’s been a lot of work done from
the view of what have we done as a community and what do we know you know I
said in my title that we know so much about this disease well this is a this
is a pathology schematic this is actually done by Jenn Parsons who I was
at Hopkins with and she was the artist there and this is the way a normal
pancreas looks and what she shows is over those 20 years when you get the Kay
wrasse mutation and the other mutations this normal pathology becomes dysplastic
and transformed into cancer and you have the right amount of mutations that
happen and then this pancreas is it becomes pancreatic cancer and this was
all done before 2000 and then after 2000 we had all these fancy next-generation
sequence strategies you hear about all these genomes being sequenced
there’s hundreds of pancreatic genomes being sequenced and she put forth Jen
actually became Jim Parsons – Jim Brumbaugh because she got married but
she put forth this schematic and it’s you know ask students well what’s the
difference because you know you have these mutations here and everyone says
well she drew that in blue the reality is and the point is is that it’s the
same it’s the same schematic so if we had the old-school sequencing technique
versus the new-school we’ve learned nothing about the genetics in 20 or 30
years we’re just able to do it faster so we’ve learned the same sequence over you
know you know back in the 90s about the sequence and I’m and I have a little bit
of a passion about that because my old mentored Hopkins actually put this whole
thing together and he did it all basically by hand without this sort of
next-generation fast sequencing technology so one of your distinguished
speakers I believe back in 1999 was Peter Noll he might have been at Fox
Chase at the time or pen or Wistar but I noticed that was when I was actually
looking through and learning about the lecture online
number one I became terrified because the group of people are amazing and I
thought maybe they asked the wrong Brody or something but one of the things I
came up on was one of my idols as dr. Peter Nowell who put forth this concept
of the clonal selection which is really part of my core all my core talks is
this paper that he put forward back in 1976 because it’s a really genius theory
that goes back to my whole clonal selection theory and what he sort of put
forth was is that there’s a normal cell that collects the right amount of
mutations and moves on and collects but what’s in that what’s interesting about
it is he also put forth this concept that some of these cells actually
experiment with the wrong mutations and they die and there’s this whole
selection process that has to happen in order for a cancer to arise and again we
know from recent work that this takes about 20 years to happen for these cells
to sort of experiment with the right amount of biology in order to form a
tumor and within that tumor it’s not just the fact that you have one single
clones you have multiple different clones that can actually cause
heterogeneity and he was so forward-thinking because nowadays I just
came back from the American Association of cancer research is there talking
about how this is important for drug resistance and I wanted to raise my hand
at the conference and say you know there’s this guy who talked about this
in 1976 and you know he he wrote here in 1976 in his discussion hence each
patient’s tumor may require individual specific therapy this is this concept of
personalized medicine you might have heard of and even this may be thwarted
by emergence of genetically variant sub-line resistant to the treatment so
he talks about that there’s this resistant clone I’m putting this forward
because I think for a lot of the scholars in the room and myself you know
we used to have to go to the library and go into the stacks and I don’t know if
any of the students know what stacks are but you’d have to go back and read
papers and journals back into the 70s and 80s and believe it or not some of
these things aren’t Google and there are pearls here there
are pearls out there that are beyond what’s not in Google so again one of my
one of my little old old person’s pearls there so this is a figure from a
textbook from the molecular biology of the cell and this is the reason why if
you look at the incidence of cancer over age Y basically in general except for
childhood malignancies that cancer is an age-related disease and again this goes
back to the concept of when I talked about that a normal or you know a baby
pancreas if you well you know to a older pancreas collects these different
mutations and goes on and forms a disease and that’s why it’s really known
that cancer is an age-related disease because it takes time for these clones
to form and actually emerge and present themselves clinically and this is work
done by my good friend Kristina Abu zo where what she did is some elegant work
what she did was she she signed up patients who had pancreatic cancer and
she got biopsies from them when and and surgical specimens from them when they
were actually at the time diagnosed and he she basically consented them and said
look I hope you do I hope you never see me again but if this cancer emerges
again I want to come in and biopsy it again I hope you never see me again
but unfortunately if you die you’re gonna have to consent to this I will
drive to ever the morgue is and I’m gonna remove those cancers and what she
did is on a series of patients she called it a rapid autopsy program
she had patients who wanted to dedicate their lives to science and she actually
sequenced the genomes of these these tumor cells through the lifetime of that
patient and sometimes it was just six months sometimes it was two years and
what she found was is that it won by looking at this she found that these
cancers probably took 15-20 years to rose but she also found is is that the
the right mutations genetic mutation genetic events different than other
events that happen but DNA events that happen in the DNA the ones that happen
initially were the same ones that caused other parts of the disease and there was
no selection for other genetic events that being said that all the genetic
events that happened when the patient presented with its disease initially was
the only events that were necessary and so that there was something else than
genetics that caused these tumors to recur and actually kill the patient so
we still believe because of that knowledge it’s important to know what
the genetic landscape is here and I took part in a program that was across the
country it was over 48 countries I mean 48 states where it was called know your
tumor and it was set up by Pancreatic Cancer Action Network and what we did
was is no matter what wherever the patient was whatever lifestyle they had
whatever insurance policy they they had it didn’t matter if they were diagnosed
with pancreatic cancer in South Dakota Atlanta Oregon Idaho we told them we
would sequence their tumor and what we were able to consent 1200 patients to
this and what we found was is that out of those 1200 patients we found that 27
percent of these patients actually had mutations that were actionable and what
that means is that there were drugs out there FDA approved that could actually
target these mutations and so this was pretty inspiring because these are
patients who didn’t have access to clinical trials they barely had access
to chemotherapy they would see physicians that never had seen a
pancreatic cancer before again Lakshmi Oh nicely brought up but 55,000 people
who were being diagnosed for pancreatic cancer each year even though it’s
becoming the second leading cause of cancer-related deaths in this country is
not a lot of people if you tell the pharmaceutical industry that you’re
working on something that’s affecting 55,000 people in the United States they
would hang the phone on me right because this isn’t a big
enough pool of people to care about however of those 55,000 people if you
tell a quarter of them you know what we have a specific drug that’s gonna target
your cancer I think those people and their families would be pretty happy so
we found this to be pretty interesting we published this in clinical cancer
research this past year if you want to look at those findings and one of those
things that are actionable that means things that it can target is this same
thing that saved mrs. crook is this barakatu status and this was work that I
was involved with it at Hopkins and there’s this really interesting idea
called synthetic lethality and what synthetic lethality is is this concept
of let’s take one of the chairs you’re sitting on perfect example of what
happens in a tumor if you take the chair you’re sitting on and you remove one of
the legs you’ll probably able to manage to sit on
it right and so that’s what happens in tumors that have barakatu removing that
leg probably sets the stage for them to be mutated and have cancer what
synthetic lethality is is if you remove another leg it goes down there’s nothing
you can do would be hard to balance yourself on it and so that’s the concept
of synthetic lethality and this is what we found happens in these tumors is this
is a tumor growing in a mouse and you can see it grows very nicely in the
mouse again these medics are just bred for these experiments this doesn’t have
the barakatu mutation you know so what happens is when we treat with a specific
agent against that you can see that the tumor regresses if we actually correct
whether it’s through something you might have heard of CRISPR met technology or
overexpression with the virus this gene the tumor becomes resistant to the
therapy thus proving to us that it’s that one gene and 35,000 or so genes
that actually this susceptible to the specific DNA
damaging therapy and of course we found that other drugs didn’t work as much
another example that I was part of a study that was really exciting we had a
patient who came in who was diagnosed a 63 year old female with a family history
of cancer because of that family history we went in and we sequenced her tumor we
found that she had a bracha to mutation we put her on a specific therapy in this
case something called par PARP inhibitors and basically this woman had
a complete response here and that complete response was amazing
however after a year really responding when she shouldn’t have been alive after
a month or two she recurred with the cancer and so 25
months later when she recurred with the cancer we removed the tumor and we
sequenced the tumor and what we found which was pretty remarkable is that
tumor found a way to revert its mutation back to a wild-type so the mutation that
actually probably caused the tumor got it to be sensitive to the therapy ended
up reverting back into it was a truncated mutation for the real
molecular aficionados out there and what it did was is it put it back in frame to
read it all the way to the stop codon so what we found in this woman’s tumor is
that the tumor said you know what enough of this therapy I’m gonna change my DNA
and I’m gonna ream you Tate back into a normal form so you can’t do anything to
me and that that’s what caused the tumor really remarkable stuff because from
intellectual standpoint it showed that we are truly targeting the lesion from a
humbling stem sobering standpoint we found that we needed a way to now find a
way to stay on top of it and play chess against the tumor and I’m currently
writing a grant right now with Israel to try to find ways in which to stay on top
of this so as a side note I thought I’d bring this up and watch me brought it up
that how many people in the room are either taking or took molecular
biology part of them so there’s there’s a number how many people have run DNA
agarose gels so how many people use tbe or tae Tris boric acid okay so that so
that’s bad – raise your hand there because we developed this new buffer
called lithium boric acid that you should look into and the reason the
reason I brought that up is because this this is actually me as a postdoc with a
little at least I thought I had more hair so I had bigger sideburns and this
is with my mentor Scott Kern and what what we found was is there was a decimal
point error in a protocol and because of that we found empirically that there is
a better way in which to run a DNA gel that you could actually do it in 10
minutes instead of waiting an hour – so something to look for and then we ended
it up based on this publishing a number of these papers if you’re really
interested in looking those up you can look them up and we’ve been cited in a
number of times and I’ve had patents on this as well and so we can use that to
really have this value again of potentially molecular profiling and
looking for these actionable mutations and so what are we doing with that
information well we’re setting up a clinical trial
in which we want to really over those 48 states are really over everyone we want
to capture what patient has that specific therapy out there and set up
these little clinical trials and ask the question will patients do really better
if they get this sort of targeted personal treatment going on other ways
that we’re looking at this in the laboratory is that one of these genes
that’s mutated is called P 16 I’m not going to get into the singling pathway
there but what that means is that you could use specific fda-approved drugs
such as cdk4 inhibitors this is not published we have this under review and
what we find here is that in AP 16 deficient tumor in vivo if we treat
specific FLE with this inhibitor we can slow to
more growth down compared to the controls so that’s where we’re at as far
as precision therapy is concerned I’m gonna be mindful the time I’m not gonna
go over if if I keep going too much I’ll oh I’ll go I’ll get to the end of it so
we can get to some provocative questions and discussion but really this is this
concept of precision therapy and precision oncology that I presented you
it’s pro following the patient’s tumor and trying to match that tumor and how
are we gonna make the difference here so what are the obvious assumptions that
are out there if you’re a cancer researcher or pancreatic cancer
researcher well you need to understand the microenvironment I talked about that
with the desert it grows in a desert so we need to pay attention to the desert
even if we know the actual mutations even though we do have these targeted
therapies we need to develop better targeted therapies we need early
detection so we need to move that needle backwards on that twenty years so we can
actually get patients to surgery before they become the patients become
metastatic the neoadjuvant stuff I’ll I’ll save for dr. Joe’s next talk and
that what that means is that it’s out there that maybe you should give
chemotherapy before you give surgery and we need better models and I’ll talk a
little bit about that how do we study these tumors in the laboratory and the
non obvious assumptions that I’ll end with today is we need to look behind the
genomics so the easy one of the points I wanted to get across today today is that
the reason why cancer researchers I think there’s been a little bit of a
halt in our knowledge as we’ve relied so much on the genetics so I grew up a
cancer geneticist being at Hopkins and it turns out that all that sequencing
we’ve learned the same thing over and over again and we need to look beyond
the DNA because we know the DNA is not important for selecting for when cells
leave the primary tumor and go off into other sites and kill the patient and we
need to think about rapid tumor evolution
how do we rethink and define our target so yes those tumors are growing in a
desert environment but then we start giving chemotherapy and a storm starts
coming through and everything how do though how does that you know that that
you know that sandstorm how did those cells protect themselves in that
environment you know so we have a number of different things going on that we’re
focusing on to look at this in different ongoing work with different institutions
that each one of these I could give a separate talk on and I’ll give I’ll
touch on a little bit but one of the points I put this slide in here is one
of the things I’m really excited about and I’m actually going to Portland
tomorrow to talk to my friends at Oregon Health Sciences University is this
concept of patient derived models of cancer so I brought up mouse models I
brought up cell lines some of you in the audience who are interested in cancer
research or just how do we study cancer or how do people study cancer what we
typically do what it’s been based on is that we try to get tissue from patients
but we also have mouse models and one of the things that we try to do is we have
things called cell lines and so these cell lines are cells that are grown from
a patient’s tumor and we grow them in Flass and we do experiments in class and
some people find that very artificial and so what people typically say is
there’s different models and you literally lie with the models that you
can play with to do experiments in because how if you take cancer cells in
a petri dish I I can kill those cancer cells with enough coca-cola we know if
we give coca-cola to patients that’s not going to do anything so we need to find
the right model and so what we’re doing we just got a really nice score with
Oregon Health Sciences University a two point five ish million dollar grant to
ask the question what is the best model out there and so what we’re doing is
we’re taking the patient’s tumor and we’re making these different models and
they’re and the models out there is one’s called an orthotopic model and
what the orthodontic mouse model is we take the human cancer cells and we jack
them into the mouse pancreas and in fact they actually grow out as if they do in
a human it’s kind of interesting another one is this thing you might have heard
of called 3d organoids and these are in 3d so they’re a little more than 2d they
actually grow in different layers and a matrix and it looks like this so you can
almost look like a pancreas organ on a dish and another one’s called
conditionally reprogrammed cancer cells and we’re asking the question from
clinical trials how much do these models actually replicate what happens in the
patient simply put and can we learn something from it so again like I talked
about this is really what the fields been focused on and one of the reasons
why it’s been focused on the central dogma of cancer is this DNA is because
if someone tells you just get that if you want to be a cancer geneticist
listen up this is a hundred pancreatic tumors ninety-five of them have a
mutation in K RAF’s 100 normal pancreas zero have a mutation in pancreas that’s
a on Kajin your cancer geneticists you passed the course my course that’s
called an oncogene if you have two alleles that are lost to the gene that’s
a higher frequency than in the normal that’s a tumor suppressor gene that’s
that’s cancer geneticist no one’s gonna argue with you if you find those 95 out
of 100 however when you start studying biology you start studying trends and
you start studying things that are a little bit more difficult it’s harder to
prove to people so we a scientist like to label things and because we can label
these genetic factors a lot of scientists study these things this is a
very crowded field and so I think this is just as important and rapid and so
this is what my lab study my lab likes to study when the RNA is made how is it
made into a protein and this is again for those not totally focused on biology
DNA is made in RNA into protein and this makes up the human being this is what we
study post transcript no gene regulation post RNA and I think
this is important because I think even though a lot of people have studied this
it is really what happens here rapidly not over decades of how these cancer
cells can adapt to these environment they’re not relying on genetics all the
time they’re relying on other things and so just like in life being a little
philosophical here and thinking about either whether you’re a psychology major
or other things there are intrinsic and extrinsic stressors right we all know
that the test you have tomorrow is a stress or why am I sitting here
listening to Brody talk versus your own anxiety of how much pressure am i
putting on myself I really know this stuff but I still don’t want to be
sitting here listening to Brody talk and so those come together and there’s a
selective pressure that happens and and I would say to you as an analogy that
cancer cells have this same selective pressure and it’s the survival of the
fittest who end up graduating and moving on and being successful at that time who
can go on and become clonal and then those cells actually are ready to take
on the drugs we can kill ninety two pot ninety five percent of these cancer
cells but it’s the 5% that are really good at taking care of these intrinsic
and extrinsic pressures that allow them to move forward and so this is the
protein that that we study it’s called Hur or her and what it does is it
basically responds very rapidly to stress and the way it does that is it
moves from the nucleus to the cytoplasm and it takes with it and amplifies a pro
survival Network so it’s basically in a car crash it’s the airbag that allows
the cancer cell to live and so here’s another way of looking at it we’ve
proven in a number of papers that pancreatic cancer associated stressors
basically push a button on the pancreatic cancer cell move this protein
from the nucleus to the cytoplasm and amplified this whole genome network of
of transcripts to survive under these different environments so it’s important
for evading the immunes causing metastasis chemo resistance a
number of things and I’ll I’m gonna just give you a couple of examples of things
that really show this dramatically so one of the things that we know that
pancreatic cancer cells live in is a very hypoxic environment so norm oxy is
just normal oxygen about five percent oxygen in which you know we need but
however when you look at the tumor cell the pancreatic cell it lives in 1.1
percent oxygen this is another example of that desert setting that pancreatic
cancer cells live in so if you look in the normal Norton or Maxia conditions
this is another play on the models we use this is a pancreatic cancer cell if
we give that pancreatic cancer cell a known chemo therapeutic oxaliplatin
which is you know given in the clinic everyday the this green marker here and
the blue is just outlined the cell is a marker for DNA damage it means that the
cells about to die there’s a lot of stress here okay if we put that cancer
cell into a condition that’s similar to what happens in side of patient there is
no DNA damage here none whatsoever so we found that this Hur protein was
critical for that because if we silence this Hur protein and again for the
molecular aficionados we use a si RNA molecule so in all ago targeted against
HR transcription we can see that we turn on the cells ability to die and that’s a
very dramatic view same thing happens in glucose so we know that pancreatic
cancer cells live in low levels of glucose okay and we we find that again
if you give a common chemo therapeutic under normal conditions that don’t
reside what happens in the patient we can kill the cells much like the
coca-cola on the cells however we put them into a low glucose setting these
cells don’t die this is what happens in the patient if we again silence this one
gene we can get those cells to die very
dramatic I’m gonna go through some of this stuff rather fast because in the
interest of time so the question could be is how can we use this technology and
this understanding of this Hur protein so one of the examples is is we could
actually target one of these downstream events of HuR but another example is we
could potentially target Hur so one of the things is we need to look deeper how
does Hur regulate the genome so when we talk about because I think there’s some
people some students some molecular aficionados out there when we talk about
genes when we talk about these genes what part of the genome are we talking
about that’s being made from RNA into protein so we is it how many people
think coding region so the coding region of the gene right so right coding
reading the gene makes the amino acids right so this is very simple how much of
the coding region so if this was the whole genome right here how much of this
whole top thing would be the coding region of our our genome of your genome
very small amount thank you so only this small now what’s going on
the rest of the genome here the non-coding region so the way Hur
regulates these transcripts is in the non-coding region so when you think that
these people went in sequence pancreatic genomes do you think they sequence this
part or this part they just sequence this part because why why why sequence
this part we don’t understand it right so I don’t want to sequence something I
don’t know and I can’t get funding for that so why would I do that so it turns
out that Hur regulates these genes and this part of the genome and what’s
exciting is we need to dive a little deeper so my father’s a psychiatrists
always put this joke up here for him but the reality is is what
we found is that hur regulates one of these key genes called we won and we won
was actually discovered by paul nurse who was a Nobel Prize winner and he
called it we won because he discovered I think up near Scotland and it was like
he mutated either you know bacteria or a fudge and it was it was we so we called
it we and that’s why it’s called we won it’s an important cell cycle regulator
and to cut to the story we found that Hur regulates this non-coding region of
we want and it turns out that in that non-coding region when my technician
gave me the sequence he kept saying I can’t clone it because I keep getting
this weird variant within the non-coding region it doesn’t make sense it doesn’t
match up with what’s supposed to be out there and I started saying well maybe
this is interesting let’s sequence other pancreatic cancers
let’s look at this and sure enough what we had found and we haven’t published
this we look at the a thousand a thousand gene populations a European
population in our own population to really summarize a lot of stories what
we found is in that this region of the genome again this region of the genome
we found that there is a high prevalence of the sequence in patients who either
have family members who have certain types of cancer and this would never be
discovered if we just focused on this in the box if you will region of the coding
region so the point here is through the biology we found a sequence that was
really interesting and actually could be a early detection marker for not just
pancreatic cancer but colon cancer so stay tuned for that one and I’m just
gonna end with you know really this question of HuR because if you can
target the airbag sequence if you will if you could target the airbag of the
pancreatic cancer cells so when they get the treatment and only a 5% of that the
cells can live you could actually maybe do some damage against these cells this
is just to show the way we look at things this is called
immunohistochemistry these are basically a hundred pancreatic cancers and what we
found here is that virtually 80% of them over
expressed this HuR protein when we reset them from patients so it’s highly
abundant we also found push Shultz is a talented graduate student and Sammie
Brown that during the sequence I talked about this normal to the progression
model as you go through time whether it’s the mouse or the human you get an
increase in Hur expression over time and if you actually cross Anna Mouse a Kaos
mutation with an overexpression of Hur you get more tumors and Sammy found this
and we published this this past year now this is a real fascinating thing to sort
of I’m coming I’m coming to the end here to think about so some of you heard
about CRISPR technology this is a technology basically the immune system
of the bacteria that can actually target and knock out a specific gene so what we
did is we took a number of tumors and we knocked out Hur and we knocked out Hur
and we grew them in cells that were grown in nor moxy a normal glucose and
everything and basically those those cells grew fine can anyone tell me why
those cells grew fine if this is such an important factor so the the reason they
grew fine is because they were in this norm oxic high glucose condition but
what happens if we put them into a hypoxic condition and we put them into
mice well it turns out that they don’t grow in mice when you remove the gene
and this is the cells growing here on the line why if you just knock out one
of the genes you get a little tumor growth keep both of the genes you get a
lot of tumor growth and so we did this a number of cells grown from different
patients giving us a true Trudy law giving us the proof of principle work
she did all this hard work to show us that when you silence and completely
remove Hur these cells will not grow in an animal so what we quickly did is we
screen for a number of agents that might target Hur and what Chris Schultz here
who is a graduate student in my lab what we found was a drug called
Providian pomo 8 which was an fda-approved drug in the fda in the 70s
that actually targeted pinworms and it turns out that this drug
specifically not only targets pinworms but it targets hur and so much fo this
is still available in finland and he was telling me about it one day and just to
show you how inspiring chrissa’s is one day i went by to see him and he normally
he has his Cheerios by his you know on this is this is his desk and here’s his
poster and everything and here’s his tie for occasionally when he needs but he
had this little yellow boxer and i realized he bought provin IAM online
from finland and he started treating cells and he came to me so dr. Brody the
stuff is amazing in animal or concentrations we can kill pancreatic
cancer cells this is 10 to 15 times more potent than what’s being used in the
clinic and so sure enough we use this Hur an inhibitor and we show that
they’re completely sensitive an animal or ratios we show that it actually
targets Hur we showed that the mechanism works this is called a ribonucleoprotein
in mineral precipitation when you add in the Providian pomo weight you block hu
r’s ability to act as that safety valve if you will where it acts here and
increases the survival transcript we showed that it got into cells we went in
vivo and we just showed that single doses as a mono therapy that it actually
killed tomb this is growth on the size that actually killed pancreatic tumors
compared to the ones that didn’t and this is actually the control that’s
being used in the clinic so you can see how well that’s working and because of
this we’re setting up a what we call a very innovative window of opportunity
trial so what we’re doing is be two to three weeks before dr. Yeoh takes a
patient into surgery we’re town asking them to take some pin
more medication and then we’re gonna look at their tumor at the time of
surgery and see if that pin were medication that has a fluorescent label
on it gets to the tumor and then we’re going to follow those patients out and
actually see if they have the ability to respond to this and why is this
important it’s important not just because we might have found a real drug
and a great target but it’s important because if we here all collectively used
our intellect and came out with a great target and a great idea for pancreatic
cancer it would take us roughly 15 years and a billion dollars to get that idea
into clinic if you think about all the regulations all the legwork that needs
to be done so finding something like an fda-approved drug that’s for something
for pinworms that might just get the worst toxicity is get someone some
diarrhea is I think incredibly important other ways we’re targeting this we’re
working with a company that’s not too far from here called jeana’s fear where
we’re using a nanoparticle it’s a nano carrier it’s three DNA’s mixed together
like one of those jigsaw puzzles and we can put different molecules like the
perv idiom or an SI hur tethered to it and deliver it to cells and we can do
this in an orthotopic model that we talked about and I’ll just show you the
example of what we’ve done so grace McCarthy’s injected pancreatic cancer
cells into the mice and she shows that by injecting this nanoparticle she can
target these tumor cells by just bioimaging these mice outside why
they’re still alive and then we can show that those tumor cells actually can go
to specific organs and we can treat them and that’s what we plan to do so that’s
the that’s that’s our ability to just do one single dose of NS i Hur and keep
these mice living longer we hope to bring this nano carrier treatment to the
clinic in the next couple of years so my take-home points is you need to look
beyond the genomics and the transcriptome it’s obviously I believe
in the genomics that was the first part of my talk we need to think about how
rapid tumor evolution and how to rethink and redefine our targets just looking at
the genetics and how they form over 20 years is enough we have to think about
as a hospital as doctors when we treat these can
ourselves we’re putting a selective pressure on them we need to go beyond
the coding region I think this might be important so I don’t call precision
medicine personalized therapy I like to call it present focus therapy we need to
think about how these things become addicted to this type of
post-transcriptional rapid gene regulation this mechanism happens within
two to four hours after treatment in the laboratory and understanding these
mechanisms will allow us to find new targets such as Hur that I talked about
and so we have these different based on all this technology we had these
different things that are about ready for phase one trials at Thomas Jefferson
and we’re very excited about that so as mentioned from Lakshmi my my my partner
if you will my producer my patron one of my idols is dr. Yeoh here this is the
lab Samantha brown is a PhD student very talented
Alex Hebert Aditi and Leigh are both working on the DNA damage work Grace and
Chris I talked about their work and Tina they’re all trying to target Hur as well
Joe’s been with me he lost his wife to pancreatic cancer he’s been with me from
day one if you only stay with me and Monique is a is a lab manager and then
Sammy’s named my my son Ethan the lab moss mascot if you will so we’ll have
them gloved up and in the in the lab and I think next year so what needs to
happen to make a difference just end with your and thank you for your time
and your attention to listen to me I think funding funding and more funding
I was talking earlier that I want people to realize this is the greatest life to
discover and work with smart people and move forward but still out of 10 grants
that go to the NIH only one gets funded that’s for every 10 ideas only one gets
funded and I think we just need to keep you know beating the drum on this if you
will to sort of have the government put more funding back in as well as have
grassroots organizations to corta awareness I think Lakshmi inviting
to people who study pancreatic cancer for this I Admiral I love that thank you
I think this is the type of effort that people don’t focus on so I think it’s
great and then finally I just want to say you know smart young people like
yourselves in the audience who want to take on this battle with tremendous
dedication and grit I think that’s going to make the difference so hopefully I’ve
inspired you to think about maybe going to science and if it’s not science think
out of the box and do what you love thank you thank you I think a little time for
questions yes correct it’sit’s a small molecule so great
question so it’s it’s ubiquitously expressed in
music’s expressed everywhere however it’s over expressed in cancer
cells and that’s for another topic we think we know why yeah so two things so one is we think in mice
and other we find that it’s just there’s higher levels in cancer the other thing
is with the the reason we’re doing the nanoparticle the dendrimer I didn’t get
into it is we have a targeting moiety that will specifically deliver the drug
and the si-hu are specifically to the cancer cells but we think the
therapeutic window there is that cancer cells over produce the her protein
that’s why we’re interested in the first place to survive and other cells don’t
need it other cells need it initially during
embryogenesis it’s actually embryonic lethal that means that if you knock it
out into mice those mice can’t live to past early stages of embryogenesis yeah figured out it how okay so so two ways really we got at
that one is we did it we did a screen so it’s called a drug screen and typically
nowadays you can get fda-approved drugs and set up a platform or an a state to
sort of say okay I’m gonna screen a million compounds and find out a way
which one actually targets my gene so that’s a complicated molecular assay but
actually not that complicated so you can look at a plate and sort of say oh
there’s a yellow dot there instead of a green that’s probably targeting it and
then you validate it the other way is he actually just did again going back to
the stacks a literature search and he found that someone somewhere had found
that it also targets Hur in other cancers didn’t really explore it and he
also you know basically found that people had found reported in very like
not really recognizable journals that this thing might have an anti-cancer
effect and they never followed up on it so just through old literature searches
and our compound screening others who’s getting surgery and who’s not
getting surgery what’s the where’s that decision process okay so that’s a great
question that because the the so the easy answer the scientific question is
you by definition if you present metastatic that means that the cancer is
outside your pancreas the literature shows that you should not get surgery so
that’s stage three stage four so for a patient to qualify for surgery they have
to at least by imaging and pathology be deemed that the primary tumor is
encapsulated in the pancreas that’s the pathologist answer the other answer is
there’s been studies that have been shown that at a number institutions and
this actually obviously is in Jefferson but there’s a number of institutions
where patients don’t get offered surgery and that’s because the either the
oncologists or the internist or the Sergent there so you’re talking about a
place like Jefferson where they do maybe 250 300 surgeries on the pancreas a year
where there are other places not too far from here that might do three a year and
in those instances you can imagine that the system just doesn’t offer surgery
and they might not know that that patient should get surgery so a lot of
this and a lot of people believe this a lot of this is awareness and in some
ways in some places you hear a lot of stories that the patient goes you can
imagine a patient goes to the doctor they have back pain you in the end
they’re older and so the internist says you know go home did you work out yeah
oh yeah I worked out two weeks oh you must have pulled something so they’re
not getting picked up they’re not getting the next group of assays and
clinical assays like see a 19-9 and other evaluations that would pick up
that pancreatic cancer so the reality is is yes it’s based on pathology
classification but the other point as far as awareness is concerned in
education is concerned a lot of patients aren’t
being offered surgery so you had this group of sort of long-term survivors has
anybody looked at like their HLA typing or anything like that to see if they
have a common yes of a really interesting question we find that the in
this case with Margaret crook it would be probably because her abraca to
mutation there is a guy Steve Lee Chu is at Memorial sloan-kettering who is now
at Dartmouth and then there’s we published a paper where we actually
asked that question three-year survivors versus six-month survivor so at the same
time the pathology should tell them that they’re the same well what’s the
difference between them and we found some molecular markers your HLA
questions a really interesting question because what leach finds is that the
tumor infiltrate with lymphocytes are different and I think they are actually
looking at but but maybe HLA is a possible reason why that’s happening or
at least an immune biomarker but that’s a really interesting question it’s it’s
an intense line of research of why do we have long term versus short term
survivors and you know a honestly other than the answer of luck at this point we
don’t have the answer and it’s the reality it’s a great question yeah it’s
the probability of getting a pancreatic cancer the same across this globe or
there are populations that are much lower or much higher yeah so a nother
interesting question so yeah so the the main the main factors that increase your
risk of pancreatic cancer I believe to date I’m not you know I’m not an
epidemiologist is the smoking and obesity so smoking seems to increase
people’s risk significantly and so does obesity interesting enough we found that
people who were obese though and got pancreatic cancer they actually did
better on chemotherapy probably based on some of the data we showed because they
have higher glucose around the tumor and so the chemo
works better but it’s mostly smoking culturally Ashkenazi Jewish population
because of the brachot two mutations they have a higher prevalence they’re
not just only predisposed more to breast cancer and ovarian cancer but also
pancreatic cancer there’s a slight increase in the african-american
population we’re part of a study with Hopkins trying to do the gene
genome-wide sequencing to see if there’s any correlation there in a multi
variable analysis but there’s really nothing that you know there’s the high
population in Japan so we’ve kind of ruled out diet who get who get
pancreatic cancer so it’s mostly smoking obesity and and some some subcultures
like you know you know Ashkenazi Jewish african-american but otherwise nothing
really sticks out are that questions anybody else is it you are yes friend of
mine had four children and her daughter died at a very young age of breast
cancer and her son then died a couple years later for a young age of
pancreatic cancer and she heard that there was a relationship yeah
not Jewish not Ashkenazi at all what so I mean you know the prom you want to
look at the foal what we say family pedigree and see if they I guess if
either the parents do get cancer or if the grandparents got cancer but yes
there is a relationship so prostate breast ovarian pancreatic those genes
what we call the the bracha one bracha two or the DNA damage repair genes all
have a connection to those tumors and so they’re not only predisposing patients
to cancer and they’re probably carried the mutation is inherited but it also
allows for those tumors to be susceptible to some of the drugs that I
showed the middle of the talk but it they
should probably see a I mean it sounds already like they should probably see a
genetic counselor and they can all get tested that’s the best thing to do you
know or at least meet with them and see and typically nowadays if there does
seem to be prevalence within the family insurance actually pays for the genetic
testing he’s a Jew or a tumor promoter yes
so it’s pro on pro s not just under stress conditions but we believe and I
went through that data really fast that it cooperates with K wrasse mutations to
actually cooperate and cause pancreatic cancer everybody has this sequence
everyone has it with it we’re all born with it and and as to your earlier point
it probably allows for us to deal with daily stressors but then the tumor cell
takes that network and uses it against us the size of this protein it’s 36
killed on I believe it was the Braca mutation had
reverted back to its original wild-type has that ever been seen before with any
other type of like the genes where the cancer actually completely reverted back
to the wild-type or at least been observed and yeah so that that was when
we published that that was the first time in pancreatic cancer but it’s been
shown in ovarian and breast cancer that they’ve specifically those genes bracha
one abraca two can revert back and it actually was initially found someone
alan Ashworth took cells and in one of the ways we studied and resistances he
grew those cells in this therapy for weeks and weeks and the cells that
emerge he went in sequenced and found that they revert it back so it’s it’s
pretty remarkable because it actually shows you that the cancer genome is able
to mutate like that in such a way to become resistant yeah just saying it seemed
counterintuitive to me that you had a mutation in Braca why reversion I should
say back to its normal state yeah and that gene was originally driving the
cancer then why are you still getting cancer so my great it’s a great question
so my my theory about that is that when you talk about the lifetime of the tumor
and how the initiation happens that mutation is probably important for that
moment in time so the analogy I tell students is it’s like that event and
their adolescence was probably really important but when they’re 35 years old
that event may not be as important and so that mutation initially it’s a genome
maintenance gene probably allowed the cells to become hyper mutable and
discover other mutations and by the time the tumor got what it needed it probably
didn’t need that mutation anymore and so it probably said okay fine you know I’m
gonna revert back to it and I’ll be fine because I had my whole networks already
set up so that’s the theory but typically speaking yes in normal
experimental settings if you revert so for like p53 bracha to if you actually
correct that in a cell with CRISPR or something else those cells will die so
it is it is kind of counterintuitive but that’s our hand waving answer yeah and that’s a great criticism we did
you know we sequenced the normal no no we sequence the other normal you know
the other panel of cancer genes we didn’t find anything else but certainly
there are probably other what we call passengered mutations that happen and so
the thing that I usually say appropriately to your point when I
present that data is you know this is an n1 however it’s in a patient so it’s
more powerful than you know doing it ten times in a petri dish but your points
well-taken I agree interested in in in early diagnosis and so you know similar
to the vogelstein model of colon cancer you’ve got various stages various
mutations going on so I guess one possibility might be or do you think
about since there’s clearly some genetic relationship in terms of you know
different generations for example my father died from pancreatic cancer so
maybe I should be tested for some of those K rats and other kinds of things
not necessarily doing the entire population but if there’s a tendency
having somebody in your immediate family or whatever that’s had pancreatic cancer
maybe they should as an initial you know early detection approach looks for some
of these other changes from the chaos of course to its yeah yeah so yeah this is
a really interesting line of investigation now and so there’s a cat
there’s a skullcap study at hopkins mike Goggins and mimmo kantos running and
what they do is they’re doing exactly what you’re saying is so they’re taking
high risk families high risk individuals who they have identified this mutation
with I mean if it was just I’m not saying just like it’s just but you know
within your family pedigree if it’s just your father you probably don’t have and
inherited it’s usually the definition you have to have first to first degree
family members who died pancreatic cancer to be true truly
defined as familial so in your instance if that’s just it then it’s and you know
you probably you know you wouldn’t get the insurance to pay for your but for
these high-risk individuals what they’ve done is they’ve done a intense screening
process and initially they found that the screening didn’t matter that they
couldn’t stay on top of it even if they screen patients and gave them endoscopy
s for every six months however the recent data that Mike showed as he
showed that if he can identify these patients early we start treating them
early enough we can increase their survival I don’t think they’re curing it
by the standards that I mentioned at the beginning but they’re actually staying
on top of it because you know like from four men when we get PSA test prostate
specific antigen there is a screen there women you know mammograms other things
there’s nothing really for the pancreas and again going back to the fifty five
thousand people each year insurance companies are not gonna pay for us to
get C a 19-9 or MRIs or other things to get done I will say dr. Yeoh when he
gives a talk sometimes he talks about I’m not sure if he does this but he
talks about like you know if he had all the money or we had all the money
insurance how the money will we get an MRI every year and he claims he says
sometimes that he does and I’m not sure look pretty screening yeah and I you
know but to that point even with the current technology we have for imaging
and early detection that’s not great and so even when we detect there’s a tumor
some people believe that those stage one stage two patients because we’re talking
about those were stage one stage two patients that only had one to two
percent cure rate right so some people believe that that’s not even stage one
stage two that we need to move the needle back even further and so that
might have to do with our imaging and early detection so if we can get a blood
test like this we one sequence or some imaging that’s better
we would probably make a big diff in this disease the Pancreatic Cancer
Action Network about two or three years ago said they wanted to double the
survival by 2020 it’s 2019 now and we moved from six to seven – eight to nine
percent five-year survival so I love them I’ve gotten two grants from them I
support them I love that they went for it but it will be interesting to see how
they pitched that coming 2020 because I’m not sure we’re gonna double the
survival but one way to do it the reason I was one way to do with the early
detection I why some patients are more responsible to gemcitabine treatment and
not others what is the reason the role of HuR and gemcitabine
so we initially published on that and then as an interesting academic note
we’ve disproved it and published against it because what we found is in our small
population we went and expanded it to a larger population and one way to
actually disprove yourself is to redo something to do it in a larger
population but that’s part of being a scientist and I tell the guys all the
time it’s important for us to get it out there so no one else does but why does
certain people so the standard of care I didn’t get the standard of care for
pancreatic cancer now is just chemotherapy it’s non targeted therapy
it’s throwing the kitchen sink at the tumor so it’s either gemcitabine
Abraxane and these are just big DNA intercalators and they just effects up
full furin ox excel a platen v a few these are things that just generically
target a number of things in a Cell if we knew why certain patients a lot of
people put forward by these are biomarkers to tell us how which patients
would do well and we haven’t found a good biomarker for that and I think if
we could find that out that’s another way we can increase survival time
because we waste a lot of time treating patients on therapies that don’t work I was wondering is there a physiological
basis why this cancer is so rapidly fatal it’s a rapidly fatal yeah I to
keep with the theme I think it goes back to the fact that we detect it so late
and so when you compare it to other cancers so two things I think it’s
because it’s we detect elate and because of the theme I had out there that it’s
it’s grown in such a harsh environment with the low glucose and the hypoxia
that when we treat it I think in some ways we get those cells stronger and
they get more aggressive and they kill other tumors are just they don’t live in
that type of environment so we can treat them a little bit easier there’s this
tumor micro-environment you know when I talk about the fact that only 30 percent
of the tumor that you resect is actually the tumor cells it’s surrounded by these
other different types of cells so to get a drug into those tumor cells that one
is even harder as well so there’s all these lists of things that make it
really difficult and faster you know I think the biggest reason is is we detect
it so late what what actually is killing the patient physiologically Oh
physiologically it’s it’s it’s the tumors growing in other settings and
totally destroying and you know the organ so in some instances you know you
could it affects the pancreas in the sense that it could cause someone have
diabetes severe of diabetes it could obstruct certain things so the person
becomes jaundice and so they need a stent put in to sort of survive but it’s
really these micro metastases that go off into the liver and other things that
cause a dysfunction and cause cachexia that you know allow certain organs to
just fail can you picture the hur protein as the
basis for an early detection test it seems like would be a cheap assay you
know compared to DNA assays and you wouldn’t have to actually go in there
and take a piece of the of the organ you could probably find it the blood yeah
it’s an it’s a really interesting question because my colleague has found
that hur is in things called exosomes that are released in the blood and so
his we haven’t published this paper yeah but we’re publishing a paper in which we
show that hur is released by cancer cells and exosomes into the blood and
the end part of the paper is potentially we can capture it and detect it as an
early detection mechanism that’s very new but it’s it’s certainly something
we’ve thought about and and certainly things that could regulate could be
things that we could detect and hopefully and the sequence that it binds
that sequences in someone’s germline so we could potentially detect it in
someone’s blood and see if they have that difference in that sequence for
instance that we one sequence yep this is sort of off the cuff but I
know there are available methods that you could when you take a blood test and
you get some of this DNA that’s been cast off by the pancreatic cells there
are ways to use DNA testing to find out whether they’re pancreatic cells versus
other cells yeah I think you’re talking about circulating tumor cells so that
people can capture in their blood to see if they’re not a whole cell I could talk
to you they’re just just DNA circulating DNA using methylation yeah you can do
that or a specific – yeah answer cells they haven’t a lot of people are
studying that but it hasn’t been proven yet I mean hopefully it will be but we
tried it with K wrasse and we didn’t have a high sensitivity or success rate
but it’d be great if it worked or looking at or looking at the methylation
status well I know people are looking at that yeah okay sure always happy to talk
about are there other questions for dr. Brody you know where to see him after
this lecture students follow him persistent as if that is the question
follow up with him and that’s the way you will be one of he is one of the role
models for you so you will be one of him tomorrow if you persist and follow okay
on that note please give him a big experience

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