Dr. Gary Kupfer, Pediatric Oncology Research
April 13, 2008
Welcome to Yale Cancer Center Answers with Drs. Ed Chu and Ken Miller. I am Bruce Barber. Dr. Chu is Deputy Director and Chief of Medical Oncology at Yale Cancer Center, and Dr. Miller is a Medical Oncologist specializing in pain and palliative care. He also serves as the Director of the Connecticut Challenge Survivorship Clinic. If you would like to join the discussion, you can contact the doctors directly at canceranswers@yale.edu or 1-888-234-4YCC. This evening, I will be sitting in for Dr. Chu and Dr. Miller. I am happy to welcome Dr. Gary Kupfer. Dr. Kupfer is Chief of Pediatric Hematology and Oncology at Yale School of Medicine.
Barber
Gary, let us start at the beginning. Where did you go to
college, and where did you receive your medical training?
Kupfer
Well the first place that I got an appreciation for cancer and
taking care of patients, was when I was an undergraduate at the
University of Florida. That was where I first started working in a
laboratory in cancer biology, back when I was a sophomore.
Barber
Did the science grab you at first or was there a personal reason
that you got involved in cancer research?
Kupfer
I've always been someone who is interested in a lot of different
things, and the idea of doing cancer research in the laboratory,
but also having the ability to combine that with taking care of
patients, is what really attracted me.
Barber
So you decided to go to medical school. Where did you do that?
Kupfer
I went to Baltimore, to Johns Hopkins University, which really got
me started and interested because it is a place that has a great
tradition of training both physicians and scientists, and molding
those two together.
Barber
Then what happens generally is that you start to narrow things
down, you go through medical school and then you pick a
residency. What did you do for your residency?
Kupfer
I went to do my training in pediatrics at the Children's Hospital
in Philadelphia, again a place that has a long tradition of
training academic physicians.
Barber
Did you know then that you wanted to be involved in working with
cancer and children, or were you thinking pediatrician at
first?
Kupfer
I really conjured both of them in my mind, and the idea of
combining multiple professions under one roof, that is academic
pursuits in the laboratory and also taking care of children, which
I have had a great affinity to for many years, was very exciting to
me.
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Barber
It is amazing work to be able to do, for really the most
vulnerable population.
Kupfer
Absolutely, and also just the idea of being able to interact with
kids is a great joy everyday.
Barber
I find pediatricians are always quite wonderfully social beings
and love to be with the kids. Then you focused more on blood
diseases, correct?
Kupfer
Actually, pediatric oncology and hematology are joined as a
subspecialty, for many reasons, one is because the most common
pediatric cancer out there is leukemia, which of course is cancer
of the white blood cells specifically, so it is representative of
why hematology and oncology have been joined under one roof.
Barber
Me being a layperson, tell me a little about your specialty.
Kupfer
Pediatric cancer, oncology and hematology, doesn't represent a
very common disease. In fact, only about 15,000 to 20,000
patients a year get diagnosed with having cancer in the pediatric
population in this country. They are around 50 times less
common and less frequent than adult cancer. On the other
hand, you can imagine what happens when a child gets cancer within
the family. It is obviously not just the patient, but it
affects parents and extended family.
Barber
I am aware of this because friends of our family just went through
this exact experience, and it is absolutely devastating. That
is a great way to start, as you describe it. It is fewer
cases than adult cancer, but for a child it can be a situation
where you have a child that is vital and active and doing amazing
things even, and then all of a sudden they are in the hospital very
sick. The family, and as parents, you are devastated, but you need
to soldier on and help this child get well.
Kupfer
That is exactly the way we put it to the parents. It is
absolutely the most devastating moment of their lives up until that
point in most cases, and you have to marshal the forces together
and make it clear to the parents that they are part of the team.
They are just as important to their kid getting better as the
doctors, nurses, pharmacists and all the other people that are
taking care of their child. They are just as important
because the bulk of the time that goes into the care of that child
is spent at home. It is really critical for parents to be on the
same page as the rest of the medical team and active participants
in their child's care.
Barber
I have heard great things about what goes on at Yale with respect
to setting up a support system. You have a team approach, but there
is also setting up a system of support. Walk me through what
the procedure is when you do have that tough conversation with
parents and say, here is the diagnosis. What are the basic
diagnoses that you work with, and then take me through what
happens?
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Kupfer
The two most common diagnoses that we encounter are pediatric
leukemia and brain tumors. Together, those two diagnoses make
up about half of the patients that we take care of. Actually,
it turns out that a great deal of lead-up time is spent in order to
figure out what a patient might have. Again, these are
relatively rare diseases, and therefore we take a great amount of
care to be sure what we are dealing with. That means a variety of
different diagnostic procedures, and again, a team approach, which
might include the skills of a radiologist, a surgeon or
pathologist, all of whom have to work hand in hand to get a hold of
biopsy of the tumor or analyze a sample that we sent to the lab
after a bone marrow sampling. So, everybody really needs to
work together. In fact, we have a number of conferences where
we get together in order to discuss the diagnosis and to be sure
what we are dealing with. There is a great deal of
preparation and lead-up time that goes into, as you put it, that
very difficult conversation that we have with parents.
Barber
You are interacting with a family physician who has noted
something wrong and has sent the child to you for a diagnosis.
Kupfer
Absolutely. As you can imagine, with pediatric cancer being
so rare, this is not the sort of diagnosis we can detect early in
the same way one might be doing breast cancer self-exams or yearly
exams for prostate cancer. This is indeed picked up in most
cases in the primary care provider's office, either through a blood
count done in response to an acute illness, or the pediatrician
picks up an abdominal mass. We are almost always referred patients
where the pediatrician has detected some problem.
Barber
It is so rare that I would imagine there are cases in which you
find that it is not cancer.
Kupfer
That does happen, and believe me, we are more than glad when that
does happen. We are also very aware that we have to be ready to
take charge and to help these families through what is definitely a
devastating diagnosis and help them realize that there is a great
deal of hope out there for the families and their children.
Barber
Let us back up a little bit. Tell me about how you came to join us
here in New Haven at Yale.
Kupfer
After my training was completed at Harvard Medical School in
pediatric cancer, I took a faculty job at the University of
Virginia, where in addition to taking care of patients, I opened up
my laboratory in cancer biology. But an opportunity arose here to
take charge of the pediatric oncology program, and I was attracted
by the idea of joining a medical school in which there is just
incredible depth and breadth of cancer research going on, which
actually fit in very nicely with the particular cancer research
that goes on in my laboratory. I was very attracted for
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that reason. There is also an incredible amount of energy here in the Yale community, with the construction of the new Yale Cancer Center Hospital and an incredible surge of activity going on in building both the clinical and the scientific research arenas.
Barber
I would imagine that doing research, something I know very little
about, but from what I have read, it really involve a lot of
collaboration, does it not?
Kupfer
Absolutely. It becomes clear when one is doing work that you
really have to rely on people, not only for research materials, but
also for the interchange of ideas. Some of the most fruitful
scientific interchanges I have had come over a cup of coffee or
just leaning against a wall in the hallway talking to
colleagues. It really is important to have colleagues with
whom you can talk, with whom you can have informal interchanges
with.
Barber
The setting in the lab I would imagine it that you are mainly
doing kind of mundane work, and then all of a sudden there is that
"Wow" moment. Is that true, are there moment with people
high-fiving?
Kupfer
I would say that those high-five moments come extremely
infrequently. The norm is more that it is very tiny building blocks
one after the other, in fact, building blocks that are based on all
the little blocks that are placed by numerous people all over the
world. We go to meetings, we read literature, scientific
literature, and we try to learn from each other. No one has ever
accomplished great things in the laboratory in a vacuum. It
is all based on people who have done work over many years.
Barber
That is interesting, you hear about this medical conference or
that medical conference, and that is why sometimes Ken or Ed can't
be here, but that notion of doctors and researchers giving talks,
as a situation that may inspire you, is fascinating. Is that kind
of the way it works?
Kupfer
Absolutely. I have certainly gained ideas in my research by
listening to other people give their talks on their own research,
but again, it comes from informal meetings, meetings in hallways,
over cups of coffee and people making little strides over many
years and adding them all up together. People work together and
form groups, and bring it back to the clinical side. There is
probably no better example of people making little strides and
adding them up over the years, as a great advancement Spain made in
pediatric cancer treatment. If you look back into the history
of pediatric cancer treatments, 60 years ago every patient with
pediatric leukemia died. There was 0% survival.
Barber
And that was just 60 years ago; 0% survival.
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Kupfer
It is a great example of a medical miracle when you think about
it. People have these very negative connotations and ideas of
what chemotherapy means. They think about bald people, people
throwing up all the time, but in fact, chemotherapy in pediatric
leukemia specifically, has meant going from 0% survival, in the
specific case of pediatric lymphoblastic leukemia, to around 80% to
85% survival in the year 2008. It really is an amazing story
but that did not come overnight, it came from little building
blocks of people getting together, working together and forming
national groups. People were treating all their patients in the
same way, and then putting all the data together in order to figure
out new and improved ways to treat their patients year after year
after year.
Barber
That is fascinating. Let us come back in just a minute and
talk some more about how we have gone from 0% survival to 85%
survival. Correct?
Kupfer
Yeah, around 80%.
Barber
80% survival in only 60 years, and we'll talk about how those
building blocks work. You are listening to Yale Cancer Center
Answers.
Barber
I'm happy to be joined today on Yale Cancer Center Answers by Dr.
Gary Kupfer, who is joining Yale. How long have you been at
the Yale Cancer Center?
Kupfer
I have been here six months.
Barber
Welcome to New Haven.
Kupfer
I am finding my way around finally.
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Barber
It is great to have you here. You have a great reputation
for pediatric cancer research and you actively explore how deficits
in the human genome lead to cancer. Let us finish up first
what we were talking about before and then go into the genetic
component, or maybe those two things tie in together? Let's go back
60 years ago, what were some of the first things that started to
cut away at those very difficult figures of losing 100% of patients
with that particular kind of leukemia? What happened first
and then what is going on now?
Kupfer
It was the realization of the use of chemotherapy that really made
these great inroads into the treatment of pediatric cancer,
pioneered by people like Dr. Sidney Farber at the Dana-Farber
Cancer Institute, where the first clinical remissions in childhood
leukemia were achieved. Then again, it really required the
cooperation of pediatric oncologists all over the world. They were
cooperating these national groups where people all agreed they were
going to treat patients in the same way, and not be selfish with
their information, but rather put it all together with everyone
else's information and then figure out statistically what would be
a better and more rational way to go.
Barber
Give me a little background on chemotherapy. Had it been
used more on adults before that, or was chemotherapy fairly new 60
years ago?
Kupfer
It was still fairly new. In fact, some work in chemotherapy
was being done at Yale New Haven Hospital, using agents which came
out of World War I; the mustard gases which were used on the
battlefield. Some of the earlier work on mustards in
chemotherapy was actually done right here, but some of the other
new chemotherapeutic agents were pioneered by Dr. Farber up in
Boston.
Barber
Dana Farber Cancer Institute has a great reputation, but it is
interesting to hear now why it has such a good reputation.
Dr. Farber was really the first one to start having success with
this?
Kupfer
That is right. But back then, his first idea of course was
using one drug to treat patients. Although you could put a patient
with leukemia into remission, where you could not see the leukemia
anymore, it was clear that only one drug could not cure a patient
with leukemia, you had to add other drugs together with that one
drug. It really was an example of what is true about cancer; it is
a disease caused by defects or changes within the genome.
This kind of leads us back to what you were getting into, which is
how cancer is a problem with changes or defects in the genome,
changes in critical genes within our DNA leading to either a growth
advantage or cancer or a decreased amount of cell death in that
particular tumor.
Barber
It always comes down to this and is what you guys are always
wrestling with, there genetic abnormalities that you are born with,
and also environmental factors. Is that a good way to put it?
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Kupfer
It is always good to remember that we all are born with one
disadvantage in terms of leading to cancer. In fact, we all
have a major risk factor. 100% of us have the risk factor of
aging. Aging leads to cancer.
Barber
Okay.
Kupfer
We all have a lifetime risk of about one in five of getting
cancer, in those terms, cancer is part of our normal biology.
Down on the molecular level, if you think about the way our DNA is
made and managed within each cell of our body, there is actually a
fixed error rate in the way DNA is managed and made, so much so
that cancer is actually thought of in that way; cancer is a part of
our normal biology. That is why aging, which represents
potentially an accumulation of genetic change, goes hand in hand
with cancer.
Barber
Tell me about what it is that you have learned on the genetic
level when a child gets cancer.
Kupfer
Because children are undergoing such rapid growth from the time of
conception in utero, all the way to birth, and then in the first
years of their lives, it is clear that in order to have growth you
need cell division and to have cell division, you have to have
duplication of your genome, indeed of your DNA. It goes back to the
idea that there are fixed error rates that go on with your DNA that
you simply cannot avoid. Now, we have very elegant means of
preventing those errors and screening for errors, but even with the
best systems of preventing errors, there are still going to be
errors that sneak through, and they are unavoidable.
Barber
Talking about chemotherapy, what is actually going on there?
Kupfer
There is actually a wide range of different chemotherapy
agents. Some of them directly inhibit the way DNA is made and
some of the drugs chemically modify DNA leading to the destruction
of the cell triggering cell death. The whole idea of
chemotherapy is not to use one means of subverting the cell, but
multiple means because at its very heart, very nature, cancer has
originated from a cell that has found a way to escape the means of
regulating cell growth. That means that cancer cells have
been able to avoid regulation, and once it does that, it has
already become genetically very able to avoid means of dying.
Barber
It is a rogue agent.
Kupfer
So it actually has a greater means of adapting to being killed by
a particular agent.
Barber
Because it is operating off on its own now, is that the way you
are putting it?
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Kupfer
In many cases it is able to genetically adapt better than your
average cell, just by its very nature of having escaped our normal
means of cancer prevention.
Barber
Is what you are working on now, the correct combination of these
agents, or are you looking into trying to develop new agents?
Kupfer
The basic things that we work on in my laboratory go back into the
tradition of cancer research, looking at these rare genetic
diseases of cancer susceptibility. We are working on a particular
genetic disease called Fanconi anemia, and Fanconi anemia is of
interest to us because although this is a rare disease, these are
children who are born with a greater susceptibility to getting
leukemia, and if one looks at the history of cancer research, we
have learned a lot about not only cancer, but normal biology by
studying how and why genetic diseases lead to greater incidence of
getting cancer. In this particular disease, Fanconi anemia,
we have learned that these patients are born with defects in DNA
repair and surveillance of the genome, and by having defects in
repairing their own DNA and defects in their genome, that triggers
a greater incidence of getting cancer.
Barber
How much is the human genome project helping your work?
Kupfer
The genome project has revolutionized what we, and pretty much
everyone in the world does, and that is there is really no gene
that is not heard of sitting in a database somewhere, it is a
matter of going there and finding it and pulling it out. It
has traversed a lot of technical problems that people have had in
pulling out DNA sequences. It has narrowed down the amount of time
that it takes from understanding potentially what genes are
involved to actually being able to study them. You can pull
out whatever genes you want to look at within a matter of days
versus a matter of months or years that it used to take.
Barber
How much information do you need to narrow it down so it's not
like searching for a needle in a haystack?
Kupfer
One gets clues from other people's work and colleagues with whom
you are actively working together on projects. You realize that
every good research project that answers a question only leads to
more and more interesting questions down the line.
Barber
This has been so fascinating. I understand this a lot better
now. It sounds like really exciting stuff. There have
been such amazing strides in 60 years, and you must be at a point
now where things are really rolling. What are looking to
accomplish in the next two or three years?
Kupfer
Our work on this genetic disease is really focused on the very
basic biology of the disease, and how that basic biology causes
cancer, and also what normal role it plays in our cells. What we
have learned from this genetic disease is that patients with the
disease have problems dealing with genetic damage. We are
learning ways to try to adapt that to make cancer therapy more
effective. In addition to our very basic studies on this
genetic disease Fanconi anemia, we have started a parallel project
in order to tweak DNA repair systems in cancer cells. We have a
very active project going on, which we hope to use clinically in
the next few years, to make resistant cancers more amenable to
cancer therapy.
Barber
So you are finding agents that change the way cells react?
Kupfer
Absolutely, and in this particular project I am talking about, we
have adapted a protein made by a virus in order to subvert the way
cancer cells are resistant and turn them into sensitive cancer
cells, make them more amenable to treatment.
Barber
It is amazing that when we talk about agents, that it starts with
mustard gas, 60 years ago.
Kupfer
Actually, going back farther it would be about 90 years.
Barber
So you continue, based on all these conversations, to look at what
things have been found that are going to turn off, or go after,
those rogue cells so they cannot do what they want to do.
Kupfer
Yes, make a cancer cell become more open to being treated using
standard chemotherapy. It is amazing the landscape of cancer
biology right now and the means of trying to treat cancer.
There are all kinds of new and interesting ways that people are
devising to try to get at particular cancers. We may have to
fashion and tailor a unique way of attacking cancer for all the
variety of different cancers, and cancer of course is not just one
entity. It is many different kinds of diseases.
Barber
Dr. Gary Kupfer it has been really interesting speaking with you
today, and I applaud your work. We started this by talking
about what a devastating conversation it is to have with the
parents, but you know, having folks such as yourself and your team
working on these diseases, it is going to make me sleep better at
night. It has got to be exciting for you just to be able to do this
for people.
Kupfer
I have one of the best jobs in the world, and that is getting to
take care of patients, work in the lab and teach. It is a great
job, a job which is intense at times certainly, but one which I
think is a great privilege to have and I enjoy very much.
Barber
Thank you for joining us on Yale Cancer Center Answers. We wish
everyone a safe and healthy week.
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