Cancer Answers: The Biology of Lung Cancer, October 17, 2010

Katerina Politi, PhD, The Biology of Lung
Cancer
October 17, 2010Welcome to Yale Cancer Center Answers with Dr. Francine Foss
and Dr. Lynn Wilson.  I am Bruce Barber.  Dr. Foss is a
Professor of Medical Oncology and Dermatology specializing in the
treatment of lymphomas.  Dr. Wilson is a Professor of
Therapeutic Radiology and an expert in the use of radiation to
treat lung cancers and cutaneous lymphomas.  If you would like
to join the conversation, you can contact the doctors
directly.  The address is canceranswers@yale.edu and
the phone number is 1888-234-4YCC.  This evening Francine and
Lynn are pleased to welcome Dr. Katerina Politi.  Dr. Politi
is an Assistant Professor of Pathology at Yale School of
Medicine.  Here is Francine Foss.Foss
Let us start off by having you tell our audience a little bit about
what cancer biology is?Politi
Cancer biology is the science in which we try to understand which
genes are involved in the process of tumor initiation, so what
starts off the tumorigenic process? What genes are involved in
tumor maintenance?  What is required for a tumor to survive
once it has already formed, and what leads to tumor progression?
What leads to the development of metastases? In cancer biology, we
also study the interplay of different cell types within the
tumor.  These cell types form what is called the tumor
microenvironment that is made up, for example, of immune cells,
blood vessels, and connective tissue.Wilson
This is obviously a fascinating field.  Could you tell us a
little bit about your background and how you became interested in
studying cancer biology?Politi
I studied biological sciences at the University of Pavia in Italy,
where I grew up, after which I came to the US and got my PhD in
Genetics and Development at Columbia University in New York. 
After that I went to do a post doc at Memorial Sloan-Kettering
Cancer Center in New York where I worked in Harold Varmus' lab, who
is currently the Director of the National Cancer Institute.  I
became interested in cancer biology early on during my studies
while I was in university, when I began to learn about genes
involved in cancer and how these alterations in these genes and
cancer cells really disrupted the circuitry within a cell.Foss
Katerina, you talk about cancer cells and tumor biology, could you
tell our audience what the relationship is between cancer cells and
tumors?Politi
Of course, cancer cells are what make up a tumor.  So each
tumor is made up of many-many different cancer cells.Foss
Is it true that those cancer cells may not all be exactly
identical?Politi
That is true, one of the ideas is that you have a genetic event
within a cell that gives an advantage, a survival advantage, and so
that cell begins to grow and to proliferate, multiply, but then
those other cells can also acquire other changes and this is
actually one of the major problems in cancer biology. We will talk
about it a little later on as well, but even when you have a tumor
that is made3:30 into mp3 file 
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up of many cancer cells there may actually be different populations
of cancer cells with different changes within each individual
tumor.Wilson
Are there particular areas of cancer biology research that are
happening now that are of great interest to lots of different
investigators, or is it one or two areas, or many, can you talk to
our audience about that?Politi
One of the things that we have seen emerge has been in the past 20
or so years.  There was a focus on understanding the circuitry
that I was talking about before, within the cells, so how do the
different pathways in a cell lead to proliferation and
survival.  What are the genes and proteins that make them up
and how do they function? Now we understand much better how these
are altered within cancer. What is happening now is that there is a
lot of focus on understanding the full compliment of all of these
changes that happen within each individual tumor.  This goes
into looking at the genomics, so sequencing the DNA, understanding
all of the changes in individual tumors, and then one of the things
that we can also do is we can work on interfering with these
changes. A large focus of research right now is focusing on
understanding how we can interfere with individual changes within
each particular tumor and this is something that requires not only
the cancer biologists sitting in their lab, working alone, but it
also requires a team effort in which the cancer biologists are
talking to the oncologist, talking to the surgeons, talking to the
pathologist, so that we can study individual changes within each
tumor.Foss
That is one of the major changes that I have seen in cancer biology
in the last 15 years or so. A long time ago we thought about a
cancer cell and investigators focused on a single mutation or
oncogene in that cell, and now when we talk about many of these
cancers, we see these very complicated network diagrams that
involve lots of different pathways, some of which are even normal
cellular pathways and how they impact on the development of cancer,
so we are at a completely different level of complexity now.Politi
Absolutely, that is correct and one of the things that is happening
is that now what has been done at various institutions and for
certain tumor types, is that at the time when the tumor is
diagnosed that tumor is then tested for a whole array of genetic
changes, and then treatment strategies are then been devised to
interfere specifically with the specific types of alterations that
are found in that tumor.Wilson
There is a tremendous amount of research going on here in cancer
and cancer biology and obviously with the new construction of the
Smilow Cancer Hospital there are lots of exciting things going on
here. Was that part of the attraction for you to come to Yale?
Obviously you have done a lot of your training and developed a lot
of your career in New York.  How long have you been here and
what made you make the change to come to New Haven?Politi
I actually arrived here in July, so just a couple of months ago,
and I was really attracted to come to Yale because of the really
great faculty and basic sciences and the great clinical faculty,
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this commitment at Yale to further cancer research and treatment
and it was a great place for me to start my lab as a junior
investigator because this translates into a very dynamic scientific
environment where communication between scientists and clinicians
is encouraged, where there are cancer biology seminars that have
been organized and there are also plans to train students in cancer
biology and resources are being allocated to cancer biology. 
So for someone whose lab is in this field, this is a great moment
to come here at a place where the foundation, the basic science,
and clinical foundation is so strong.Foss
Katerina, I understand that cancer biology isn't necessarily a silo
organization that you cut across, as you point out, multiple other
disciplines and other areas around the university.  Can you
talk a little about how you integrate with other departments who
perhaps aren't necessarily studying cancer biology, but are
studying important pathways and mechanisms that could compliment
your work?Politi
There are two aspects to this, one of them is that I can work with
people in various basic science departments, for example, one of
the genes, and I will talk a little about it, that I work on is the
Epidermal Growth Factor Receptor gene, and so when we study this
gene and when we study mutations in this gene, we really have to
understand how these mutations alter the structure of the protein,
and so there we will interface with the structural biologist, for
example.  At the same time, some of the things that I work on,
I develop genetically engineered mouse models of lung cancer based
on these EGF receptor mutations and so we have to figure out ways
in which we can actually visualize the tumor, so then we will talk
to people from the imaging departments for MRI imaging, for CT
imaging, PET imaging to see if we can visualize these tumors and
even develop ways in which we can specifically view EGF receptor
mutant tumors.  So those are just a couple of examples of how
the work that I do requires this really strong foundation in the
basic sciences that there is here.Wilson
You have mentioned lung cancer, be a little more specific with us
about what types of cancers you study and within those, what sort
of work you are doing?Politi
I study lung cancer.  Lung cancer can actually be divided into
two main histological groups.  Small cell lung cancer and
non-small cell lung cancer.  Now, non-small cell lung cancer
makes up 80% of all lung cancers and this can be further subdivided
into three histological subtypes; lung adenocarcinomas, squamous
cell carcinomas, and large cell carcinomas.  Lung
adenocarcinomas actually develop at the periphery of the lung in
contrast to squamous cell carcinomas, which instead develop more
centrally in the central airways, and lung adenocarcinomas are
rising in incidence and that is believed to be due to the increased
use of filtered cigarettes which actually allow people to breath
the smoke in more deeply, so carcinogens from the smoke reach the
periphery of the lung more easily. My work focuses on studying
genes that are mutated in lung cancer and so what we know is that
even though lung adenocarcinomas may look very similar when you
look at them under the microscope, they can actually be subdivided
into different categories based on genes that we know are altered
in these lung adenocarcinomas, and one of the11:38 into mp3 file 
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 genes that is altered in about 10% to 15% of lung adenocarcinomas
in the US is called the Epidermal Growth Factor Receptor gene and
this gene is actually mutated most frequently in lung
adenocarcinomas that arise in people who have never smoked.
Importantly, tumors with EGF receptor mutations are more sensitive
to treatment with specific drugs that have been developed during
the past several years that block the activity of the Epidermal
Growth Factor Receptor protein.Foss
So Katerina, the Epidermal Growth Factor Receptor is an important
element on normal cells as well, and the distinguishing factor with
the tumor cells is that this particular protein is mutated.Politi
That is right, and so the Epidermal Growth Factor is present on
human cells and it is one of these proteins that actually will
sense cues from the external environment telling the cell whether
the cell should survive and multiply or whether it should not, and
in the case where it is mutated, it does not know how to regulate
these signals anymore and so it is always active.Foss
Let me ask you the key question then, in nonsmokers who have an
increased expression of this mutated receptor, how does that
mutation happen outside of the setting of smoking which obviously
exposes the lung to carcinogens?Politi
The answer to that question is really not known at this point.Foss
Is that something that you are looking at in your research as well,
are you focusing on how those mutations happen?Politi
I actually am not working on this in my laboratory, there are
certainly groups that are trying to understand why this is
happening and, for example, one of the things that we know is that
there is a higher frequency of mutations in lung adenocarcinomas in
Asians in the EGF receptor and so one of the possibilities is that
there may be some environmental factors that may actually give a
higher frequency of these mutations, but this is an area of active
investigation, nobody knows the answer.Wilson
Thank you Katerina.  We are going to take a short break for a
Medical Minute.  Please stay tuned to learn more information
about cancer biology with Dr. Katerina Politi.15:04 into mp3 file 
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of surgery at Yale Cancer Center is a video-assisted thoracoscopic
surgery also known as VATS procedure, which is a minimally invasive
technique.  This has been a medical minute more information is
available at yalecancercenter.org.  You are listening to the
WNPR Health Forum on the Connecticut Public Broadcasting
Network.Wilson
Welcome back to Yale Cancer Center Answers.  This is Lynn
Wilson, and I am joined by my co-host Dr. Francine Foss. 
Today, we are joined by Dr. Katerina Politi and we were discussing
cancer biology.  Katerina, tell us a little bit more about the
mouse models with lung cancer that you have developed.  Tell
us what you do when you get into work or into the laboratory
everyday.Politi
When I developed the mouse models of lung cancer that I'll tell you
about, we had just discovered EGF receptor mutations and the group
I was working with it at Sloan-Kettering discovered these along
with other groups in Boston, in particular, and Tom Lynch's group
when he was at MGH as well, and so what I really wanted to do is I
wanted to understand how the mutant EGF receptor is changing the
biology of the tumor cells to cause cancer, and so to do this I
decided to develop these mice in which I could actually turn on a
copy of the mutant EGF receptor in the lung and see what happened,
and in fact, what we can see is that these mice develop lung tumors
and they closely resemble the lung tumors that have EGF receptor
mutations in the case of human cancer.  Importantly, what we
can do is we can also visualize the tumor using imaging like
Magnetic Resonance Imaging or CT scans and we can test the
different drugs on mice that have tumors to see how effective they
are at getting the tumor to go away. So the drugs that are used
clinically now in humans, also work very effectively in these mouse
models of cancer.  One of the problems with drugs that are
used to block the activity of mutant EGF receptor in the clinic, is
that they work initially, but drug resistance inevitably
emerges, so drug resistant tumors develop so we
have used our mice to develop a model of resistance to these EGF
receptor inhibitors.Foss
Can you expand a little bit on how you interact with the medical
oncologists who are treating lung cancer patients? How do you
connect your work on drug resistance to what is actually happening
in the clinic in patients?Politi
Ever since I started working on lung cancer at Sloan-Kettering, we
had a group there of thoracic oncologists, surgeons, pathologists,
and scientists and we were trying to figure out what the important
clinical questions related to lung cancer were and how we could
answer those questions in the laboratory, and this type of approach
will continue here at Yale as well. We're actually putting together
a translational lung team to work on problems in lung cancer and so
one of the examples of how our mouse models are very effective is
that we, in collaboration with William Pao, a scientist and
thoracic oncologist who is now at Vanderbilt, developed a mouse
with EGF receptor mutant lung cancer that was resistant to
treatment with these drugs that are used in the clinic, and we
tested various different new drugs and drug combinations and we
found one combination that works really well in the mouse models.
The tumors shrink very rapidly and so this is the basis for a
clinical trial that is now starting at sites that include Memorial
Sloan-Kettering, Vanderbilt, and Yale, so this is how rapidly this
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tested things in the genetically engineered mice and are moving on
to the clinic to help people who need effective treatments
fast.Foss
The important thing about what you are saying is that historically
when we've combined therapies in the treatment of cancer patients,
we have not necessarily had a strong rationale for combining
them.  We have not had these kinds of molecular models where
we have been able to show in a mouse tumor system that combination
is better than either drug alone, so that is certainly a giant step
forward.Politi
Now our knowledge of what is happening in the individual tumors is
really helping us figure out what we need to do to block that tumor
from growing.Wilson
Regarding the mice, do you have to do anything special to their
immune system to make the model work, or are they completely normal
mice?Politi
The mice that we use actually are immune-competent mice.  So
their immune systems are completely normal, and this is actually
very important and is different from what has historically been
done to test drugs, in fact, pharmaceutical companies historically
use xenograft models and what that means is that human lung cancer
cell lines are injected into mice that do not have a normal immune
system, otherwise the mouse would reject the human cells, and the
tumor is allowed to grow, and one of the problems is the immune
system is a very important component of tumor formation, whether
the immune system is functioning or not can modulate tumorigenesis,
and so one of the advantages of using the genetically engineered
mice that I am talking about is that we are doing these experiments
in the context of an intact host, so everything is functioning.Foss
So again, a major step forward in cancer biology compared to the
way we used to do things. Are there other major advances in cancer
biology that you can tell us about?Politi
There are advances in terms of our knowledge of what is happening
within the individual tumor.  One of the big projects that was
undertaken by the National Cancer Institute, I am thinking of the
cancer genome atlas in which we sequenced tumors of different types
and we are not only sequencing them to see what mutations there
are, but we are also looking at how the levels of genes change, how
the levels of protein change and trying to integrate all of this
information so that we can really get a full picture of what is
happening in each individual tumor.  One of the other big
changes that has occurred is that formally a lot of drug discovery
would happen within the drug companies and now as we are learning
more about the molecular pathology of tumors and about the specific
changes and we have very good models even within academia, and our
technologies are better, we can actually do a lot of drugs
screening even within an academic institution and so it is not
unheard of for the development of drugs to actually start within
universities.Wilson
So you have mentioned lung cancers being related to smoking, people
smoke the lung is exposed23:38 into mp3 file 
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to smoke, we can understand how cancer can develop in the lung, and
you, in very basic terms describe for us what sort of differences
are you aware of when we have a lung cancer that originates in the
lung compared to a tumor somewhere else that may spread to the
lung.  You know, when I take care of a lung cancer patient
often those cancers are generally in one place or may spread to the
lymph nodes nearby, sometimes spread to other parts of the lungs,
but in some patients I have taken care of who have a cancer
elsewhere in their body, it may spread to many different parts of
the lung.  What is it about the cancer biology of these cells
that makes one tend to behave itself sort of in an isolated way and
another one perhaps spread very aggressively throughout the same
kind of organ?Politi
 Even within lung cancer, for example, there are many different
tumor types, so there is a
 situation in which there is a type of bronchioloalveolar
carcinoma, which is a sub-type of lung and adenocarcinoma pneumonic
BAC, which actually spreads throughout the whole lung field as
opposed to, for example, focal tumors where there are cases in
which you can have multiple primaries occur within the lungs. 
We really do not know very much about what the differences are
molecularly between these different tumor types.  Now that we
have a better grasp on the molecular changes that occur within
different tumors, we will see more of a focus on trying to
understand these more complex issues in cancer biology that we
could not understand or really even began to grapple with
previously, like studying metastasis. Going back to your questions,
one of the thoughts is that their may be a subpopulation, let us
say within a breast tumor that metastasizes to the lung, there may
be a subpopulation that goes through the blood stream that has
acquired the ability to grow in the lungs, for example, and so that
is what may be happening. It goes through the blood stream but it
has acquired some genetic change or epigenetic change or something
that allows it to spread through the blood and then survive in the
lung.Foss
That gets back to a point we made earlier in the show which is that
tumors are not necessarily a homogenous groups of cells, as you
mentioned there are multiple different aberrant pathways that could
be expressed and they can be different within the same tumor.Politi
Yes, that is right.Foss
I wanted to ask you a little bit more about your EGF receptor work,
and lung cancer of course isn't the only tumor that over expresses
EGF receptor and I wonder if you could talk about some of the other
tumor types and how applicable your findings in lung cancer are
going to be for some of these other tumors as well.Politi
The EGF receptor mutations in these specific types of mutations,
have really only been observed in lung adenocarcinomas and
very-very rarely found in other types. Over expression of EGF
receptor, on the other hand, has been found in other tumor types
such as colon cancer and once again, there are drugs that target
the EGF receptor that are used in colon cancer, for example the
antibody to the EGF receptor, cetuximab, and so similarly there you
have a specific change in a gene that is driving tumorigenesis and
so when you block the activity of that specific gene, you27:45 into mp3 file 
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 are blocking the ability of that tumor to survive.  That is
very similar.  The problem is that the EGF receptor inhibitors
that work on mutant EGF receptors in lung cancer, do not work as
well on high levels of EGF receptor.  They have a better
affinity for mutant EGF receptors.  So, those drugs cannot be
used, for example, in colon cancer.Foss 
 That is an important point for our listeners who might be familiar
with some of these drugs or read on the internet about some of
these new agents. Even though it is EGF-receptor associated, it may
not be applicable to their specific kind of cancer.Wilson            
 You only been here a few months and obviously thought a lot about
the future, what sorts of things are you looking forward to in your
work here at Yale?  What sort of opportunities do you see in
the future or in the short term?Politi
I am looking forward to working with the translational lung cancer
team here.  I am very excited.  When I was in the process
of choosing to come to Yale, I met a lot of people and there is
great work in setting circulating tumors cells, stem cells
inflammations, serum changes in lung cancer and so I am really
looking forward to working together with this group, it is a very
exiting time.  There also have been, in the past couple of
years, several cancer biologists recruited here, junior
investigators, and so it has been exiting to get to meet them, and
talk to them about research.  I am very much looking forward
to working together with them.Dr.Katerina Politi is an Assistant Professor of
Pathology at Yale School of Medicine. If you have questions or
would like to share your comments, visit yalecancecenter.org where
you can also subscribe to our pod cast and find written transcripts
of past programs.  I am Bruce Barber and you are listening to
the WNPR Health Forum on the Connecticut Public Broadcasting
Network.