THE CANCER QUESTIONS PROJECT: Larry Norton, M.D.


we were treating acute myeloid leukemia
in 1977 with seven and 3 (right) we are still doing the same in 2018, my question
is what is the best way forward to change it by 2028. I think the big problem is that we get stuck with our language that we use to describe
diseases and the language starts influencing our thinking rather than the
thinking influencing our our use of language and what I mean by that is
leukemia is a disease of abnormal white-cell proliferation and we use
terms like hyper proliferation for example increased cellularity for
example and those terms convinced us that we’re right that that’s what it’s a
disease of and we’re not thinking about the big picture
we’ll take solid tumors which I know much better and you know in this in this
regard you know clearly prefer Asian is is an important component if cells don’t
divide they’re not going to have too many cells but when you look at your
average breast cancer it’s as percentage of dividing cells is lower than a
gestational breast for example so it’s not cell division that’s the problem
and and yet nevertheless we use the same terminology and therefore we get stuck
with anti-mitotic drugs seven-to-three is an anti-mitotic regimen and yes indeed
we kill cells and we try to drive toward killing all the cells which actually is
mathematically impossible that’s the goes back to Howard skipper
and it goes back to and Howard skipper worked on leukaemia leukemia 1210 was
the primary model that Howard skipper Frank Schabel Griswold and colleagues
really looked at in that in that setting and and they proved with proportional
cell killed that you can’t get rid of less cell it’s actually impossible
mathematically impossible these drugs kill a certain percentage of the cells
that are present not an absolute number and as you decrease the absolute percent
the percentage more and more and more you still left with residual population
so other factors are coming into play that’s giving to cure of leukemia and
those other factors are probably cell-cell interactions microenvironment
changes and so on which we can spend hours who are they talking about so is
the disease proliferation or is the disease a
a Miss functioning of that complex of the leukemic cells of white cells with
other cells in its micro environment and are we just treating the obvious thing
which is the cell division part without treating the real root cause of the
disease occasionally we get down to small enough number that those other
factors play a role but should we be looking at those other factors and this
is certainly true in solid tumors where our cell kills are much less than we
achieve in leukemias and lymphomas so we have to broaden the definition I
mentioned earlier self seeding as one phenomenon of you know cancer so cell
mobility is as important to cell division but there are many other
factors involved and it’s the communication between the various cells
that make up the tumor that or the abnormal marrow for example in the case
of leukemias is that we really have to address parler a problem is that because
we were convinced or we convinced ourselves that cancer was the disease of
of cell proliferation we developed experimental models that screen drugs
for the inter prolific effect and we also developed clinical trial designs
that assess the activity of our agents by the amount of cell kill and we didn’t
look for some of those other other phenomenon and and that really is a real
problem because if I say like in breast cancer that I have an anti metastatic
agent how do i testing if I metastatic Asian if I can’t make a cancer shrink
and I measure duration of that that shrinkage I can’t get approval of that
drug there’s no clinical trial methodology that looks for anti
metastatic agents and yet if anti metastasis anti summability
is a key to making progress I’m not screening drugs for that I don’t have
mechanisms of screening drugs for that and I certainly don’t have clinical
trial designs so I think that we really have to sort of get away from being
stuck in the notion that cancer is a disease of cell proliferation and not
only think about other things which many people are doing now certainly not the
only one who’s thinking in this direction but developing the tools for
being able to screen drugs for that activity and also test them in a
clinical trial environment thank you Larry what three and a half million
papers published in cancer 135 thousand in 2017 alone there is a staggering
distance between great scientific insights into the biology of the disease
and our ability to translate this into them improve treatments for everything
what are we doing wrong I think we’re doing a lot of things wrong and first of
all you know great science is not necessarily great science that’s going
in the direction of improving prognosis for our patients that’s that you know
you can have great science as beautiful science and and we love it for the
beauty of the science but that’s not necessarily getting us in the direction
we have to go I am a big fan of basic science and I think that’s really where
all the fundamental ideas come from but we also have some selection factor for
the ones that may actually you know help our patients with cancer is could be an
important part of that often we rediscovering the same thing over and
over and over again you know there are five enzymes to do something so you
publish a nice paper on the 6th and somebody publishes the paper in the 7th
we’re not really making an advance that could really help us in that direction
but I think that’s not the big problem I mean I you you want to see unfettered
science you want to see unfettered creativity that’s not the real problem
that I see the real problem is that we don’t have a good mechanism for getting
really important observations up to the level that we can attract the funding to
develop them as therapeutic agents or as diagnostic tools once something has
proven activity or then then the mechanisms work very very well advanced
biotech large Pharma you know can take something that works and really drive it
all the way to completion develop it as a commercial entity and deliver it to
the patients and believe the issue drug pricing out of this for the discussion
that’s another problem but but on the other hand we know that there are
mechanisms for doing that we have a venture capital community that’s
actually very good at taking things that are very promising that have reached a
certain point and developing up to the level that it can move into that other
other aspect of development what we don’t have is stuff is is is a mechanism
by which we can unleash the enormous positive power of
business to take really early discoveries and bring them up to the
level that they then make sense for a venture capital kind of investment for
venture capital investment you want to see 10 times or more return on
investment in a fairly short period of time what about things that take a
little bit longer or have a lower return on investment because they’re higher
risk to move them forward there’s no real way of getting money into that
process from a very early stage up to the stage that people can actually think
it’s a reasonable thing to invest in because at that level your choice start
invest in a drug or invest in better running shoes or invest in something
else that makes that make sense from an economic point of view I’m talking about
from a human point of view rather than strictly an economic point of view now
from an economic point of view obviously a win as a win as a win a very good drug
that could be you know brought to the public that’s going to be successful for
everybody involved but but how do you get it up to that point and we haven’t
solved that problem yet that’s that’s I think one one of the biggest problems
that we have to face is is is how to get very early things that are very
promising that a very high risk and what I mean by my return on investment you
don’t have to win each one let’s say have 10 projects and one of them really
pays off well that one that pays off you know then could the other nine could
fail and you still can make a reasonable although not adequate from a VC point of
view a return on investment to be able to move it forward so you need we need a
lot of research and we also need ways of taking some of the most promising things
that are high risk and developing to the point that the the existing economic
mechanisms of business development for for agents can really take over and and
and and we don’t have that I’ve seen over and over again really great ideas
just die because they can’t reach that point I mean just do a certain amount
with grants and the hundreds of thousand dollars you need you need a few million
dollars to take it to that point and we just have no mechanism for getting that
so so I think the biggest advance that I could see foresee in terms of actually
curing cancer is not a scientific discovery we’ve got plenty of that going
on what we need is a better business model and and until we solve that
problem some of our very best ideas are gonna die on the vine very unique answer question number three
the fact that children respond to the same treatment better than others of
course suggests that cancer biology is different yes also that the host is
different now if that is the case since most cancers increase with age even
having good therapy may not matter because the host is detected well I
wouldn’t say decrepit I think that may not be the proper the proper term
obviously it’s different I think but I’ll just give you a very good example
something we’re working on right now is that with single cell sequencing and
microdissection we’ve absolutely proven and published with extremely good
authors and extremely careful controls that that the majority of breast cancers
primary breast cancers harbor mutant white cells and those white cells have
known oncogenic mutations and so and so we actually have leukemic cells that are
that are concentrated in the cancer we also find that a very high percentage of
people with all cancers have clonal matter polices they have these mutations
that are circulating in very low tigers in their in in their circulation but
those cells in breast cancer at least and we’re looking right now at lung
cancer we’re looking at colon cancer those cells are concentrated in the
cancer so they’re doing something and if you want a and hypothesis is that what
cancer is is a mutant epithelial cell a solid tumor a mute epithelial so and a
mutant why so and they shake hands and they both grow into a tumor
the tumor is is much these mutant white cells that is the the mutant epithelial
cells and it may be due to the fibroblasts
maybe mutant endothelial cells that’s all work that really remains to be done
well that’s obviously a phenomenon of aging as you get older you develop
mutations and your normal tissues we know this for sure them the most most
mutated tissue in the human body of the eyelids almost nobody puts suntan lotion
on their eyelids exposed to UV radiation lots and lots of mutations on eyelids we
know this from from published work and as we get older we develop mutations in
our white cells all of us after certain age have mutations in in our bone marrow
we don’t have all have leukemia thank God but on the other hand they’re there
and they may be doing something if you have a random chance the right mutation
in your white cell by random chance the right mutation in
your epithelial cell and they support each other then they together form it
form a tumor and that’s really what forms of cancer nobody ever died of
breast cancer cells would you die as tumors and tumors are complex ecosystems
of many different cell types now that’s very different than the
pediatric situation where the we have driver mutations and we’re discovering
more and more driver mutations and it is a disease of hyper proliferation and is
a disease with the cancer cell itself is is is the abnormal feature and the
microenvironment may be much less important and of course if cancer is
disease of cell division we’ve got very good drugs that that kill dividing cells
of course we developed them that way it’s my previous answer to two into
another question and of course they work better because that circumstance because
the model applies in the pediatric situation but the model may not apply in
the adult situation and to assume it does leads us into the situation we are
today where we have great responses and we don’t have great cure rates for many
diseases so I think we have to expand our thinking and in the expansion of our
thinking come up with novel ideas and also develop a business model so we can
take those novel ideas and develop them to the point that the conventional
mechanisms are commercial development can take over and we can have better
therapies for our patients limitless well first we don’t need limitless I
mean there’s there’s plenty of money out there to do this it’s just not being
applied to the problem all right and I’m talking about things like sovereign
funds countries I mean there are a lot of countries out there that have
redeveloped a lot of wealth and and that wealth is being invested in generating
more wealth now why wouldn’t those countries want to be the place where
cancer is cured I don’t understand why not it wouldn’t it be really nice to
have the cancer cure from a country that has a large accumulation of wealth and
so what should be done is is that money and and I’m not I’m not talking about
really that much by by by standards of large sums of money should do what I
said it should it should get together really smart people should look for
really early ideas that are high-risk because they’re very ideas but
they’re very smart generated by people who have some kind of track record or
nor not or just a good idea of producing good things and fund them as companies
and it could be a for-profit model I don’t care whether it whether it’s a
usually they say for-profit model or it’s a venture philanthropy model or the
money goes back into the sovereign fund or individuals make money it doesn’t
matter to me but that that that it should be developed to the point that
that most of them will fail and the ones that succeed will degenerate then
generate sufficient funds that makes sense from a business model now I’m not
the one who came up with this Andrew Lowe who’s the professor of financial
engineering Sloan School of Business at MIT one of the smartest economists
around you know has actually worked out the numbers and and the numbers really
do work with sufficient money and sufficient guidance that it’s almost
guaranteed you never guarantee anything obviously in real life but almost
guaranteed that you’re gonna turn up really exciting new ideas that could not
be turned up by any other mechanism and and develop them moving forward so
that’s what has to be done we have to channel the existing funds that are out
there in the world and large hedge funds in in in sovereign funds and in other
other sources you know of money that have been accumulated and really really
used the fat power to really make a difference and it can be done the ideas
are out there I am convinced that the cure for cancer is already known we just
don’t know it and it’s sitting around and an observation in the laboratory
somewhere and it may never be developed and that’s just just an incredible
tragedy and I would also say what I said before when I started this this
conversation is that a curing cancer the same the same drugs the same approaches
may work for Alzheimer’s disease and Parkinson’s disease for for plaque of in
coronary arteries for renal disease mechanisms of damage cells surviving may
be a common mechanism for a lot of these diseases or most of them and so as we
understand the process better I mean for example the cloning amount of releases
that I mentioned the fact that we have mutant white cells circulating around
that’s a risk factor for coronary artery disease as well as a risk factor for
hematological malignancies and we’re looking into it as a risk factor for
developing solid tumors as well so all these things are connected we
have the ideas we have the people the money already exists all right it’s not
being applied to the problem so if I had and not unlimited but if I had access to
those kinds of funds setting up something like that would make an
enormous amount of sense to me and would really make a difference in the world thank you patients with a stage I think
I think the I mean that’s a very complicated question because you can’t
answer it in generality I mean that’s the kind of question that could only be
answered one on one an individual patient an individual healer one has to
define what the goals are and then one has to do what’s necessary for the goals
and it could be adding a few months of life it could be palliating symptoms it
these were all processes taking a chance on something that’s very risky but might
make a huge difference you know I saw that with taxol I mean I barely on you
know with the drug tax all had a patient who was really dying of liver
involvement with with breast cancer and and we had this conversation to go power
the care we tried this brand new drug that I have no idea if it’s gonna work
and we don’t even know his toxicities yet and she made the decision to go with
it and she got years of extra life high quality life by going to the Asian those
are the things that that stand-in in in the back of one’s mind so III think that
you can’t answer that in generality I mean it’s a very individual very
personal decision that people have to make and and and like all important
decisions that has to be made by a couple it has to be two people having a
conversation the patient who’s an expert in their life and the physician or the
nurse or the healer that’s an expert in biology and medicine and and they have
to have a relationship where in a conversation they can come up with the
right answer that’s appropriate for that particular situation I wouldn’t want to
see generalized solutions to something like that it’s a very personal very
individual very intimate a situation that that has
to be addressed and talked about in that in that context thank you amazing
loved all your answers thank you very much thank you

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