Parker Hyde – KETO-CARE Trial

Parker Hyde – KETO-CARE Trial

July 20, 2019 4 By William Morgan


– I think we are all in complete agreement
that the current state of cancer research
needs to be propelled
and there’s not a better topic
on emerging science
and nutritional ketosis
and carbohydrate restriction
than what all of these speakers before me
have kind of really been
laying out on the line.
So a lot of it is standing
on the shoulders of giants
of the people that come before me,
but I really wanna take a second
to talk about specifically breast cancer.
For me this is a more
personal type of topic.
20 years ago almost to the date,
my mother was diagnosed
with breast cancer.
So for her 40th birthday birthday,
she actually got a
breast cancer diagnosis.
And when I was eight years old,
I started trying to learn
all about breast cancer
as I could.
So that really sets us up for the talk
that we’re gonna talk kinda have today.
And then we’ll get in a little bit to
what the KETO-CARE trial is,
the phase one clinical trial
that we’re currently running
here at Ohio State University.
I got two clicker like everyone else did.
So I feel like I would be remiss as a
more of a clinical oncology researcher
to not at least have some
seer database information
from what the current landscape
of breast cancer really looks like.
So approximately 250,000 women
were expected be diagnosed
as new cases of breast cancer
in the year 2017 alone.
So that number, if you take
a look around at your table,
it’s about one in eight or one in six,
it depends on what research you look at.
Women will be diagnosed with breast cancer
during their life.
So that’s on average,
one individual at each one the tables
if they’re filled with exclusively women
would be diagnosed breast cancer.
That’s a number that’s incredibly shocking
but at the same time
it’s somewhat comforting
because our diagnosis rates
are getting a lot better.
Our diagnostic technology
is getting a lot better.
And I think that we
can all agree right now
that the Think Pink movement
has been incredibly influential
in the breast cancer landscape.
You look at the NFL and every single year
they have a Think Pink month
or they have a breast
cancer awareness month
where all the players wear pink gloves
and pink shoes and everything.
And that’s really exciting.
But what it doesn’t touch on
is metastatic breast cancer specifically.
So I really want you to take a second
and look at these last
two numbers forming.
So the median survival in a woman
that is diagnosed initially
with stage four breast cancer
is 26.9 months.
26.9 months,
and then you take a look at the estimated
five-year survival of a
woman that’s been diagnosed
with stage four breast cancer,
and it’s 26% make it past five years.
Those numbers are absolutely abysmal.
The first time that I,
like my first semester, when I got here
working with Dr. Volek
we were writing grants.
I was sitting at the kitchen
table, I was pounding away
and these are like the
first three sentences
you put into any grant proposal right.
You have a prevalence rate,
and you have a diagnosis rate
and a prognosis.
I sat there, I typed it all out,
and I had to kinda take a second,
sit back and kinda go, “Holy cow.”
Like this is the impact of the research
that we’re trying to do
and this is something that
is touching so many women
at each time.
So, everyone’s well
aware of how much funding
goes into breast cancer.
You know, there’s been a lot of
allusions to some of the
poor management of money
and everything,
but there’s a lot of
money that gets dumped
into breast cancer,
approximately $15 billion
has been invested in
breast cancer research
from the years 2000 to 2013.
I think the scariest aspect
of that to me personally
is less than seven percent of funding
actually makes it in the
metastatic landscape itself.
So what’s so wild to me is that
these are the women that tend
to be dying from the disease.
And unfortunately as Dr.
Champ referred to it earlier,
this is not a curative base cancer.
So most of these women,
when they’re diagnosed,
their oncologist never use
the word cure with them.
It’s not a curative dose ever.
So most of the chemotherapies
it tends to be like a two
percent complete response right.
So almost never do you
actually see a pure cure
in stage four breast cancer.
And that’s something that
kinda like hits you right in the feels
and you kind of instantly bond with women
as soon as you start
dealing with patients.
Because, well you can’t
directly understand
the struggle that they’re going through,
you want to be there as much as you can
on an emotional level.
And I think this is something
that we really need to try,
not just as ketogenic researchers
or carbohydrate restrictive researchers,
we really need to try to push the envelope
in terms of metastatic specific disease.
And I think all the ketogenic
researchers here right now
are working on advanced stage disease
in some form or another,
which is fantastic.
But that’s not happening in every other
type of cancer research right now.
So just a couple of
quick facts to orient you
with what genetically breast
cancer really looks like.
It depends on where you’re
looking at for your data
but approximately 90 to
95% of the occurrence
of breast cancer is not
due to heritable traits.
So they’re non-heritable based mutations.
This is something that
occurs across the lifetime
of an individual.
So this is normal aging.
You might get mutations
that occur with this.
It could be an environmental
factor that you’ve run into
that has this caused some sort of mutation
or collection of mutations
that cause a cancer
or result in a cancer.
And then I think
importantly, BRCA1 and BRCA2,
these have been highly popularized.
And individuals understand
when they see BRCA,
they know, oh that’s a breast
cancer associated gene.
In reality, it’s about one
to three percent of women
that are diagnosed have this heritable
BRCA1, BRCA2 mutation.
So it’s a very small number.
And then that last one,
I think everyone in here,
when you see this number,
your face kinda lights up
and you’re like, oh wow,
like keto can actually get it
through this mechanism potentially.
So approximately 40% of metastasis
have PIK3CA mutations.
So that’s the gene
associated with PI3 kinase.
I’m not gonna hammer too much on that,
everyone that’s gone before me
is really taken a good time to explain
the importance of PI
kinase in cancer signaling
as well as in ketosis.
And then I think these two
bullet points right here
everyone will look at and say,
“Yup, ketosis might be able to hit that.”
So postmenopausal obesity
responsible for approximately
two fold increase in diagnosis rate.
Two fold increase just by
being postmenopausally obese.
You think keto can hit that?
What about insulin resistance in obesity?
Those are both associated
with increased mortality.
Nodal metastasis, so a
more invasive disease
as well as larger neoplastic growth.
So it is a more aggressive,
it is a larger cancer
and it’s associated
with greater death rates
all because of insulin
resistance and obesity.
They are highly correlated
with insulin resistance
and obesity.
So that brings us to a
very similar paradigm
as Dr. Scheck was just outlining.
Dr. Volek, Dr. Lustberg and myself
have a paper that we
published, I think last year
kind of outlining our
hypothesis on ketosis
and breast cancer specifically.
And so kind of what we outlined is
we know that we can get
a metabolic changes.
We’ve just seen that you
can change the metabolism
of a cancer cell by feeding ketogenic diet
or administering ketones.
What we also know is
that in healthy tissue
we have a vast like ability to change
and manipulate the metabolism
of the healthy tissue as well.
We know that with ketosis,
there is this chronic down
regulation of inflammation.
So we see a massive
knockdown in inflammation.
We see decreases in
proliferation and metastasis.
A lot of this work comes
from preclinical models.
And I think what’s really interesting
is depending on what view
of cancer you kind of take
and what view of cancer
metastasis you look at,
one of the leading hypotheses right now
is this concept called epithelial
to mesenchymal transition.
And so what that means is you
have a differentiated tissue,
so epithelial tissue,
it gets exposed to some sort of stress
or it undergoes some sort
of dedifferentiation step
and becomes more mesenchymal
in an appearance.
So that’s kind of
something that Dr. Scheck
started to talk about is that
it becomes almost like
a cancer stem-like cell.
So it becomes a pluripotent base cell
that might increase its ability
to extravasate and
eventually extravasate into
a distant organ creating metastasis.
As far as I’ve read,
a lot of the kind of
preliminary evidence on this
seems to indicate that
certain inflammatory cytokines
are highly correlated with this epithelial
to mesenchymal transition.
And then lastly, some of this data
gets pulled from Dr. Fines research study.
So I think one of most
important aspects of that
is one small graph that he puts in there
that a lot of people
seem to jump over is that
sleep quality in many of
his patients was improved
which is a large side effect
of advanced stage cancer
and as well as kind of
higher dose chemotherapies.
And then there is improved
emotional functioning
depending on the certain
qualitative scales
that you actually look at.
So not only are we getting at the disease
but in a group that so used
to palliative treatment,
we might be improving
the patient well-being
at the exact same time.
So if we’re able to
synergize ketogenic diet
with the chemotherapy
or radiation approach,
as well as improve patient well-being
what it starts to look like,
and this is a great analogy from Dr. Volek
that I think I will use in
every talk I’ll ever give
is you start looking at
ketosis as just a big hammer.
And everything starts looking like nails.
So you just start knocking everything down
and that’s exactly what’s going on
with the cancer treatment
and kind of our hypothetical
views of it right now.
So all that background,
sorry for rushing through
but this is the really cool stuff.
So this is the study that we are actually
currently actively enrolling for
and have patients undergoing
and a couple patients have
already completed baseline,
baseline three month and
six month data on this.
So it’s a really exciting trial.
We think we’re kinda fancy
by coming up with a really neat acronym.
And so what it is is
it’s the ketogenic diet
and chemotherapy to affect response
to breast cancer treatment.
Makes this really glamorous
title of the KETO-CARE study.
I also wanna take a second to point out
we have a group of fantastic
Canadian collaborators
sitting right up here in the front.
Dr. Gerry Krystal, Dr. Dave Harper
and then Dr. Ingrid Alyssia.
(audience applause)
They’re our fantastic collaborators
that have been instrumental
in our ability to
really gain a significant
amount of funding
for this research project.
So what our study is is
it is a controlled trial
with 20 patients in each arm.
So we have a control arm that’s undergoing
standard of care nutrition advice.
And then we have a ketogenic arm as well.
I do wanna take note that it
is not a randomized design
we are using a self selection criteria.
We don’t think that is
necessarily the most ethical thing
or the easiest choice for an individual
to get randomized into a ketogenic diet
especially if there’s someone
that already naturally follow
something like an Ornish diet.
So it’d be very difficult for
them to go into the keto arm.
So with that, we realized
that we might be sacrificing
some of the pure RCT
wonderful façade that most
people tend to get at.
What we think we’re gonna see
some really cool results
with this is well.
What’s really cool about this study
and I hope you guys agree,
is that the first three
months of the trial
is a controlled feeding study.
So we actually have a
kitchen here on campus
where we cook and prepare
100% of the calories
that these individuals
are supposed to be eating.
Because it’s such an important study
we’re actually customizing the menu
to every single patient
enrolled in the trial.
So if they want fish
one day, they get fish.
If they want filet mignon,
we serve filet mignon.
A lot of this is headed
up, if you look in the back
all the way in the back line,
this is the rest of the Volek team
and there with me, there in
the kitchen in the trenches
preparing all the food for
these patients on a daily basis.
(audience applause)
So cool, controlled feeding study.
What does it mean in real life?
So that’s the second half of our study.
The second half is really looking
at a free living experiment.
So if we can get women
into ketosis, fantastic.
How do they do when they’re walking around
the grocery store on their own?
Are they able to buy groceries?
Are they able to state the peripheries
and actually do this on their own?
Formulate their own diet
based on the way that
we’ve kind of educated them?
And when you kinda zoom
out to 30,000 foot,
essentially we’re running
two studies in one study.
The first three months, is
there a biological effect
of nutritional ketosis in
advanced stage cancer patients?
Is there a biological effect?
The second, is it feasible?
If it’s not, if there’s
no biological effect,
what does it matter if it’s feasible?
No one’s gonna do it right?
If it’s feasible but there’s
no biological effect,
why do we care?
The next couple of slides
we’re gonna talk about
some of the baseline in
three month PET CT data
that we’ve seen with
some of these patients,
but also wanna note that we’re doing
some of the most comprehensive
immunophenotyping that’s ever been done
in this specific population,
especially surrounding ketosis
and the potential ways
that ketosis might augment
kinda the immune system of the body.
So we’re actually taking and doing
both an innate and adaptive
immune challenge using E. Coli
and herpes simplex virus.
A lot of that work is being spearheaded
by our Canadian collaborators
as well as Ryan Dickerson
who’s walking around somewhere.
He’s one of the biochemists on our team.
So I think you guys are well enough teased
that you wanna see some data, yeah?
I got double-clickered again.
Okay, so we’re gonna look
at a couple of patients
that’s three months data.
It’s only the Keto arm,
so I’m not gonna show
you comparative controls.
I just wanna really hit some
of the highlights right.
So, okay cool, it’s like
mixed up on the screen.
So what we have here is
we have a 43-year-old
African-American woman.
She is actually presented
with stage four breast cancer
on diagnosis.
She did one round of chemotherapy
or one single dose of chemotherapy
at another cancer center in Chicago,
came here because she didn’t
like the way she was treated
and now she’s undergoing
treatment at the James
or at Stephanie Spielman if you will.
She was ERP are positive, HER-2 negative.
So for those of you are unfamiliar
with breast cancer research,
a breast cancer is not a breast cancers
it’s not a breast cancer,
it is one of most heterogenous
cancers that is out there.
And so we tend to grade
people and rank people
and there’s treatment based strategies
on their histochemistry.
So that means it’s estrogen receptor,
progesterone receptor
positive, HER-2 negative.
So generally there’s a very
specific treatment strategy
that’s associated with this.
She happened to have metastasis
specifically to the liver and the bone,
and she was undergoing
a Taxane-based therapy.
She was using paclitaxel,
which she was on three
weeks on, and one week off.
So just to kinda give you
a view of what she was like
as a woman as well.
On the top, we’re seeing
baseline PET CT imaging.
Dr. Fine did a fantastic job,
I don’t want to go back
over what PET CT imaging
really looks like.
But just to give you an idea
of what we’re looking at
is how are black these images?
The blacker this image is,
the more metabolic activity,
the more active the cancer is.
So if you look, you see
cardiac tissue right here,
kidney, ureter, bladder as Dr. Fine said,
that’s all completely normal.
You also see the brain’s
lighting up pretty good.
As expected, we’ve been
here for the past two days.
These are actually metastasis
specific to the liver.
So this is a very large metastasis,
a very large lesion and then most of this
right through here’s lesion,
it gets a little convoluted
because the kidney’s
sitting right behind there.
So you’re kinda picking up
a little bit of the kidney as well.
And this is a more focused view.
If you look she already
has necrotic cores.
So there might’ve been of a
miniature effect of treatment
or a small effect of treatment
going on when we imaged her
and that’s kind of what
you’re seeing right here.
So you see a dark and then
a bit lighter in the middle.
And what I want you
really to pay attention to
is the three month data.
So I don’t have any SUVs up here,
that way we can actually
report the true data
whenever we publish the paper.
But I don’t think anyone
in here would argue
that that is significantly
less black, right?
So that’s three months of
ketogenic diet treatment
plus three months of taxel-based therapy.
So it’s this response is not
completely out of the norm, ordinary
but this was actually the first patient
and so I sent Maryam a
text, and I was like,
how excited should we be about this?
She was like, “Yeah, you guys
should be pretty excited.”
So you guys can all be
excited right now too.
(audience laughing)
Okay, so this is actually a
three-dimensional rendering
of that exact image that
I was just giving you.
So as you see it’ll rotate around
and you can kinda see that like
that kidney is a little,
it’s whenever you get
the full frontal view
it’s kind of making it
look a little bit worse.
The green arrow is pointing
to residual port activity.
So there’s a little bit
of dose still on the port
when we infused the dose.
All the blue is pointing to
those liver-based lesions.
And something that we all
thought was really cool
that made us have like a holy crap moment,
was the heart is there at baseline,
we no longer have heart.
And that’s something that we’ve seen
in every single imaging
at three months, six.
So the heart completely drops off.
So we’re using almost exclusively ketones
and not esterified fatty acids is
what we tend to be thinking.
So we’re moving forward in discovery
specifically on cardiac
metabolism as well.
So also, this was done with
average ketones, at 0.6,
an average blood glucose of 90.
So it was not extremely
restrictive ketogenic diet,
but she was well within the
range of nutritional ketosis.
Next two slides get a little bit crazy.
So what this is is this
is dynamic imaging.
So we are basically able
to create a flipbook
of PET CT imaging across
the first 15 minutes.
So we create a movie file.
This is just a screenshot
on the next slide
and you can see it’s one
of the busiest figures
I’ve ever tried to present my entire life.
So there is an orange circle right here
that kind of masks and
mirrors this orange lesion,
which is one of those primary
liver lesions we just saw,
and the blue is doing the same thing.
Over here you’re gonna see a
kind of change in perfusion
of the cancer and then,
some of like the healthy tissue,
the dose will drop off
and you’ll see the
lesions continue to grow.
I’m telling you it’s a really busy slide.
So, wait for a couple of seconds,
when it hits 15 minutes,
right back here on this bottom corner.
So, boom, it goes down
the descending order
the liver fills, the liver’s perfusing,
it’s going back out.
And you can slowly start to see
that each one of these
tumors is starting to take on
quite a bit more FDG.
So they’re still highly
metabolically active
as compared to the rest of the background
which is not as metabolically active.
So it’s really testing perfusion.
And what we’re gonna do eventually is
calculate the exact
metabolic rate of the cancer
at that time.
And then this is quite
important of a slide.
I think that just looked
at it went, “Whoa.”
So this was one of our patients.
You can see she had quite
a bit of liver lesions
at the start of the diet.
This is a patient that
has been on chemotherapy
and been on several types
of drugs prior to this
with a stage four diagnosis.
Hadn’t really seen any great improvements.
At three months following
ketogenic diet and
Xelota which is like a capecitabine,
it’s a precursor to 5-FU.
Try to find the black.
Just for everyone, the
radiology report said that
there is minimal detectable
difference between
the previous lesion sites
in any sort of background parenchyma.
So it’s almost impossible to distinguish
what the cancer has done on the liver.
There’s still a couple of
hypermetabolic sites on the bone
at this time.
Average ketone, 0.53.
So just over the nutritional ketosis line.
Average blood glucose was about 105.
I know I ran over, last slide.
So this is a testimonial
from that previous patient.
So I want everyone to take a second
and read this, read it really well
and then, we can have a discussion
during this round table with
all the rest of the speakers
about how important this is
not just from a physiological standpoint
but from an emotional
standpoint at the same time.
For anyone that’s been around
someone going through
chemotherapy or radiation,
it is a very passive experience.
You kinda go in, you have an IV,
you get the drug pushed
or you have radiation
therapy administered.
Whenever you’re actually sitting there
able to physically do something yourself
that you can buy into and feel
that you have an objective
biomarker looking at
such as ketones,
it really helps kinda
reinforce why you’re doing it
and the patient’s really buy in.
They really love it.
And I think these last two sentences,
my most recent scan shows that
my liver mets have regressed
and are almost undetectable.
I’ve lost 20 pounds without trying,
I’m off sugar without any cravings
and I never thought that would happen.
Fantastic, absolutely fantastic.
And then I wanna thank
the rest of our team here.
So Mr. GQ, Dr. Jeff Volek right now.
(audience laughter)
The rest of the Volek team
and then our British Columbia,
they’re not British Columbia
so Vancouver collaborators.
And then Dr. Knopp, Dr. Ryan Katie Gonzel,
they’re all part of the imaging team here.
And then I think we can all agree,
we can’t thank Maryam Lustberg enough.
She’s been absolutely
pivotal in our ability to
get in and interact
specifically with patients here.
And she’s kind of been the
one that I think has taken
a lot of arrows for us at Ohio State
because not once has anyone ever told us
we’re crazy to our face.
(audience laughter)
With that, thank you.
(audience applause)