Uncovering Insights into Cancer and Alzheimer's with Marcus Peter, PhD

Episode Transcript
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Erin Spain, MS (00:10):
This is Breakthroughs, a podcast from Northwestern University
Feinberg School of Medicine.
I'm Erin Spain, host of the show.
For more than 30 years, Dr.
Marcus Peter has immersedhimself in cancer research.
Most recently at the Robert H Luriecomprehensive cancer center of
Northwestern university, pioneeringstudies in the field of cell death

(00:34):
research and developing strategiesto selectively kill cancer cells.
He is now using the same trailblazingmethods he has uncovered in cancer
research to lay the foundationfor a new avenue of treating
Alzheimer's disease and potentiallyother neurodegenerative diseases.
He is the Tom D Spies professor ofcancer metabolism, and a professor of

(00:56):
medicine and the division of hematologyand oncology here at Feinberg and
joins me today to discuss his research.
Welcome to the show.

Marcus Peter, PhD (01:05):
Thanks Erin, and thanks so much for having me.

So let's start off by talking about cell death research.
As I mentioned, this is somethingyou've been doing for about 30 years.
Explain this research to me.

So how can we make cells die?
Obviously, there's one particulartype of cells that we'd like to kill.
The cancer cells.
So for the last 30 years, basicallyit's all been about cancer research
and how we can tackle this.
How can we overcome resistance to therapy?
How can we eliminate cancer cellswithout affecting normal cells?
And it started out with oneparticular form of cell death

(01:38):
that's called apoptosis.
It's one of those regulated form ofcell deaths, and we studied that
and we deciphered how it works, and Ilearned a lot about makes cells die.
However, more recently, last 10 years orso, I realized is that as a biologist, if
I was mother nature, why would I put allmy money on one form of cell death only

(01:59):
if I wanted to eliminate cancer cells,which is critical for survival, right?
And in the early two thousandspretty much all cancer centers
worldwide had one mission orwas to cure all cancers by 2015.
That's nine years ago.
So out of that frustration a littlebit arose a driving force: the desire
to start over and think about whatcould it be that has made us survive

(02:22):
as multicellular organisms thelast 2 billion years, basically.
And then about 14 years ago we stumbledover something that allowed us to kill
all cancer cells in a way they couldnever become resistant to this day.
And we now know when we do this,when we trigger this mechanism that
we are gonna talk about today, thenwe also don't have any measurable

(02:44):
effect on normal tissues yet.
That's not to say if it ever gets intopatient, we won't have side effects, but
so far we don't see anything in animals.
So that's how it started.
So initially it has nothing to dowith neurodegenerative diseases such
as Alzheimer's disease, but it wasthis mechanism and so we started
diving into how does this work?
It is based on short RNAs.

And you have found that these short RNAs in particular
noncoding RNAs play an importantrole in regulating gene expression
and could have implications forcellular functions, survival and
potential therapeutic strategies.
Tell me more about this.

Gladly.
So we have a number of large moleculesin cells we call macromolecules, and
they are these different classes andpretty much everybody knows about DNA.
And then there's protein.
Proteins basically is what makesall cells function properly.
And in between are certain types ofRNA, that code for those proteins.
So the DNA is convertedinto these long RNAs.

(03:44):
The RNAs give rise to the proteins thatmakes the cells function and survive.
It's important, this context.
But then there are short RNAsand they don't code for protein.
So we call them non-coding RNAs,and they have multiple function.
And a class of those short RNAs,they're only 20 nucleotides long.
These are the buildingblocks of DNA and RNA.
These short ones, they actuallynegatively regulate gene expression.

(04:08):
So basically they target the long RNAs.
The moment the short RNA, whichis a piece, sometimes a piece of
the long RNA, targets the longRNA, the long RNA gets eliminated.
The protein can no longer be made.
They will have effects on cells.
We can induce this process.
It's called RNA interference orRNAi, but nature of course invented

(04:28):
it and does it much better.
And there are professional short RNAs thatdo this, and they're called microRNAs.
And microRNAs do target dozens, sometimeshundreds of these genes in networks.
And they do maintain differentiation.
They do a lot of different functions

Thank you for that explanation.
Can you tell me more about whatmakes some of these short RNs toxic?

To understand why certain short RNAs can be toxic, we
need to understand that we have about20,000 genes in our genome, roughly and
about, again, roughly 10% of those genesare required for survival of all cells.
Of those 20,000 genes, manyof 'em can be eliminated.
You may have some effects, some responseby the cells, but it's not critical.

(05:15):
And then there is a subset of about10%, about 2000 of those genes, and
they're defined by taking one of themout in a cell and every cell would die.
And we call thoseessential survivor genes.
Now think about it.
If there's a long RNA that codes for oneof those critical survivor genes, what
would happen if we eliminated or targetthat long RNA, the cells would die?

(05:38):
So that means that over the last 800million years, at least, that's how old
microsRNAs are, all the way from littleworms to us, that there must have been
an evolution to prevent microRNA fromever targeting, attacking the mRNAs that
code for those critical survivor genes.

(05:58):
So, and that is exactly what we found.
And since the way the short RNA targetthe RNAs is only worth a minimum of
six nucleotides, it's a very shortregion that we call the seed sequence.
So if that seed sequence has acertain nuclear tech composition.
We have four nucleotides in all of nature.
And if there has a certain G richnessas we say, but only in the short

(06:21):
stretch, what we call the seed, andwe put that in any, any short RNA
and it does its thing and targetingthe long RNAs, every cell would die.
So that's why not a single highlyexpressed microns we have in
every cell, or almost all cellsin our bodies carries this code.
We call the kill code'cause every cell will die.

(06:43):
Now if you really believe in ourhypothesis, if you buy into that,
that it is that old, and thatcould be a mechanism, that would
be of course a fantastic way fornature, not only to protect us, but
also kill cells that are unwanted.
So in fact, this would be theideal anti-cancer mechanism if
you could control it, becauseobviously it is very dangerous.

(07:05):
It's very powerful and needto be controlled tightly.
And coming back to what I saidinitially, it does activate multiple,
multiple cell death pathways.
We have about 20, 30 of 'emtoday, not just one or two or
three as a few decades ago.
So now you have it.
You can activate all those in parallel.
And you can imagine once you'reattacking dozens or hundreds of

(07:27):
genes in these targeted sites, inthese genes there are even more.
How can a cancer cell everbecome resistant to that?
It would have to mutate.
Basically all these geneseliminate all these sites.
So that is the mechanism thatwe believe we discovered.
We call "death induced by survivalgene elimination", in short, "DICE."

Tell me how you discovered that these toxic RNAs allow cancer
cells to die, but not normal cells.

When we realized that we have certain types of short
RNAs that are toxic to pretty muchall cells and were super toxic
in killing cancer cells, we thenstarted delivering those constructs
to mice, to rodents in cancer models.
And yes, we had all expectationsthat those mice would drop dead
after the injection, but they didn't.

(08:14):
They're perfectly fine to this day.
So it turns out that, at least from whatwe can tell, every tissue we'd looked
at, the liver being the most importantone in this case, is unaffected.
Which raises the question, sincethose survivor genes you would think
would be expressed in all cells, likeall of us have a heart and a liver,
why would normal cells be spared?

(08:35):
And then it hit us.
It was, basically the fact that microRNAsare expressed in all cells and microRNAs
are required to maintain differentiationand maintain all of what we are.
And when you look into whatcancers do, they're the opposite.
They are de-differentiated.
Cancer, for the most part,is not really killing people.
It's metastasis.

(08:55):
90% of our deaths occurthrough metastasizing cancers.
Metastasizing cancer are theopposite of a differentiated tissue.
So then if you believe that microis maintain differentiation, then in
order to become a really good mobilehighly killing cancer cell, you
need to get rid of those microRNA.
And that's exactly what we found.

(09:16):
It's also been published by others beforeas a global downregulation of all microRNA
in all human cancers and some of thecancers they studied in rodents as well.
And that kind of opens up themachinery in the cell that
mediates RNAi in a simplified way.
And then the other aspect is thatthose survival genes, they're not only
good for survival of normal cells.
Cancer cells are under a lot of stress.

(09:39):
In order to resist that, tobecome a resilient, guess what?
They do upregulate all thosesurvival genes that we are
targeting with our therapy.
So there you have it.
You have a complex of proteins thatmediates RNAi that is open because the
protective micron is no longer there andyou have more of the targets that we're

(09:59):
targeting and that allows the cancercells to die, in normal cells, not.
And that was exactly the question,what would happen if normal cells
would lose their protection?
Again, known for many years.
There is a downregulation ofmicroRNAs in many tissues in
mammals, including humans with age.

(10:19):
So there is an aging connection.

So, why does this mechanism exist?
And why are normal cells protected?

I think we ask ourselves, oh, it's great that
we can treat mice and we can havean effect on tumors in these mice
with no effect on normal cells.
Why?
I mean, there's an evolutionaryunderpinning, there's a
rationale why this exists.
If this were a mechanism thatwould be effective on every single
cell hardwired into the cell, itwould always be limited to a cell.

(10:49):
The selectiveness between a cancercell and a normal cell would just be
at the level of what makes a cancercell different from a normal cell.
It would not explain why a normalcell is resistant to this mechanism.
So there had to be something, and Ibelieve we found it, and that is there
are endogenous RNAs in the cells thathave this coat and they are needed.

(11:09):
and these are long RNAs and manyof the long RNAs, they're, in
fact, the majority of all RNA inthe cell are so-called ribosomal
RNAs for the aficionados or tRNAs.
And they are structural RNAs.
That means they're not really regulatory,they're structural, and they have this
specific nuclear tech composition.
It's known for many years that they canbe degraded into small RNAs, and since

(11:32):
they are so hugely abundant, they cansneak into this risk complex and they
could potentially kill cells, and that'salso known that they get degraded and
enter this complex and mediate RNAi.
So we now believe, that's how natureworks, that those microRNAs are not
only maintaining differentiation andthey're very highly expressed in all

(11:53):
differentiated cells, but they're alsoprotect us from any endogenous toxic RNAs.
They're not just these micro RNAs, they'realso the fragments of these usually
abundant RNA said contain the kill code.
So that I think iswhy it evolved this way.
And fun fact that's also known formany years that these, again, for the

(12:14):
aficionados, tRNAs, are highly increasedin Alzheimer patients and when we age.
It's all published andyou put this all together.
I said, wow, that's whatwe need to protect it for.
That's why we now come in fromwith exhaustion of sources
basically put it coming from theoutside with the therapeutics.
That's why normal cell are still protectedbecause they're still busy protecting

(12:36):
themselves from themselves basically.

Are there other folks around the world
who are also studying this?
This is something that your labhas discovered and now that you're
bringing into other diseases, buttell me about around the world.
Have other folks started to look intothis type of science for cancer treatment?

To this day we have published 21 papers on this in
multiple diseases, in major journals.
And no, to this day, not a single groupworldwide has picked this up but one.
There's one group in Kentucky thatfour years after original discovery
traced our steps and did exactly thesame that we found and published it
in the context of prostate cancer.

(13:13):
To this day, to my knowledge,this is the only paper that ever
followed our path, but that's finebecause we just keep developing it.

Well, that leads me to this next question, which is you're
continuing on this journey throughcancer research and then there's
this pivot to Alzheimer's research.
How does that come about?

It actually was my wife who's in the group, Andrea
Mermann, who figured, well, if you'reright and there is this death inducing,
anti-cancer mechanism, shouldn't therebe a case where this is overactive and
shouldn't that result in some sort ofdisease because of loss of tissue, such
as neurogenerative diseases, for instance,and said, Hey, that's a good idea.

(13:52):
Since this is an anti-cancer mechanism, wefigured, well then we would postulate that
these patients may have a neurodegeneratedisease, but they may have less cancer
because the anti-cancer mechanism will beactive in every cell in the body, right?
And so she started searching andthe first thing found was a disease
called Huntington's disease.

(14:12):
Nice thing about Huntington'sdisease, in contrast to Alzheimer's
disease, has a single cause.
There has one gene affectedHuntington by an amplification of
a certain sequence in nucleotides.
And there is evidence in the literaturethat these sequences can act like
short RNAs and they're uploaded intothe complex that mediates RNAi and

(14:34):
regulate genes just like microRNAs.
When we realized that, Andy ordered shortRNAs and tested whether we can kill cancer
cells, and boy could we kill cancer cells.
This was 10 to a hundred timesmore potent than the original
ones, the DICE inducing ones.
And so we looked into Huntington'sdisease and indeed Huntington's disease

(14:57):
patients, there are multiple studiescorrected for age and everything that
showed they have 50 to 80% reducedcancers and that's all cancers.
Wow, we thought.
Maybe we should start looking to that.
So that's one of the reagentswe're developing, as a new
form of cancer therapy, theseHuntington derived super toxic RNAs.

(15:17):
Well, Huntington patients have decadesof symptom free life, and then there
is an onset and it kicks in andthen it goes downhill from there.
And that is also true for prettymuch all those neurodegenerative
diseases from Parkinson's toALS, to Alzheimer's disease.
And since here at Northwestern, wehave this fabulous collaborators, I
teamed up with the group, Bob Vaserat the Mesulam Center for Alzheimer's

(15:41):
Research here at Northwestern.
We started looking into this.
And then we tested multiple models,mouse models, neuron derived cell line
models treated with the specific toxicproteins that are believed to be the
cause of Alzheimer, induced pluripotentstem cells differentiated into neurons
and something we're gonna talk about,I guess also later the super ages.

(16:03):
And we put all this together, we realizedindeed these toxic RNAs accumulate in
the cells in this complex that mediatesRNA, RNAi in Alzheimer's, patient.
In Alzheimer, indeed, late stageAlzheimer patients get much less cancer.
Funny enough, late stage cancerpatients don't get dementia that much.

(16:23):
So there is this inverse correlationand once we did the literature
search, we found the same connectionto less cancer for Parkinson,
for ALS, for all these diseases.
That's why we got interestedin Alzheimer's disease.

So now we're gonna dive into the current study that
we're talking about today, recentlypublished in Nature Communications.
Tell me about this study some of theresults and what you were able to publish.

Yeah.
This study actually is, was based ona previous study in the context of
ovarian cancer where we looked atpatient material and mouse models,
and we realized not only can we killcancer cells with these toxic RNAs.
But when the cells become resistantto chemotherapy in ovarian
cancer, that would be mostlyplatinum based, the chemotherapy.
Then the ratio of the non-toxicto the toxic short RNAs in this

(17:09):
protein complex in the cell thatmediates RNAi, it's called the
risk complex, by the way, changes.
So in the resistant ones, you havemore of the non-toxic ones, providing
a better protection against toxic ones.
And in two previous papers includingthis one, we showed that chemotherapy
to some extent unleashes a wave oftoxic short RNAs and in part kills

(17:32):
cancer cells through this mechanism.
So we kind of knew that the ratioof the non-toxic versus the toxic
ones in this risk complex that maypredict treatment outcome, or in other
words, may predict whether any tissuewill be susceptible to this or not.
And then we had to develop this toolthat allows us, in a very standardized

(17:53):
fashion to analyze the contact ofthis protein complex that mediates
RNAi and plot it and quantify it.
And so once we had that and validatedit, we then started establishing mouse
models, different types of mouse modelsthat mimic the human disease, Alzheimer's.
We got, cell lines that were treatedwith the toxic proteins that everybody

(18:14):
else studies, which are of course ontop of this cascade that leads to the
neurotoxicity seen in the disease.
And we looked in other components,and we got, as I mentioned, cells that
arrived from stem cells turned intoneurons, and we got those actually from
Alzheimer patients and studied them.

(18:35):
And in all these cases, we foundthat in the context of Alzheimer, the
amount of the toxic seed containingRNAs in this complex is higher than
the non-toxic or the ratio shifts.
Similar to the study on the drugresistant ovarian cancer patient.
It shifted, so they becomemore susceptible to DICE,

(18:57):
this mechanism we discovered.
And when we treated the cells acutely withthis toxic protein that we know induces
Alzheimer's disease in patients, thenthat resulted in a very clear dip of the
non-toxic, the protective microRNA, that'swhy we call them protective microRNAs.
There's a clear correlation betweenyour ability to deal with the

(19:18):
stress and having the protection.

You were able to leverage these findings from your
study and apply what you foundto the brains of super agers.
Now we've done previous episodesabout super agers and the super aging
research program here at Northwestern.
It recruits and studies adultsover the age of 80, who have memory
capacity of individuals who areat least three decades younger.

(19:42):
And after they pass away, super-agersdonate their brains to the research
program to help investigators understandwhat's going right with aging as
opposed to what is going wrong.
So tell me what you found whenyou investigated your theory on
their brains of the super-agers.

It was a very preliminary study, but we got three brains
of these super ages and subjected themto the same type of analysis and compared
them to regular folks like us, right?
The non-super ages.
And it turns out, indeed, as predictedthe ratio in those brains of the toxic to
non-toxic one was taught the non-toxic.
They still have more protective ones.

(20:20):
So I think.
we postulate, we hypothesize at leastthat these people for a reason that
are unknown, aging more slowly, whichof course gets us to where we need
to take this whole thing, right?
We need to find a way to reducethe loss, to slow down the loss.
We'll probably never be able toreduce it, but the slow down the
loss of the reproductive microRNAs,a number of tissues selectively,

(20:40):
hopefully in the brain, and thatshould help with basically make us
more resilient towards getting anyof those neurogenerative diseases
or may even be helping with aging.

But there's also this idea out here that this study
could lead to new treatments forAlzheimer's, which is desperately needed.
Can you talk about that aspect a littlebit and sort of a pathway forward for
potential new treatments for Alzheimer's?

Absolutely.
That of course, is exactly theflip side of our cancer approach.
In cancer, of course, we're trying todesign the most toxic short RNAs that
have the highest selectivity for cancercells are not affecting normal cells.
Now, Alzheimer is exactly the opposite.
Here we want to either prevent the toxicRNAs if they have a major contribution

(21:24):
to the disease to do their thing.
Or we would like to increase theamount of the protective ones to
make it more resilient and maybe pushthe onset of Alzheimer's from, you
know, your early eighties to yourearly nineties, and then it may not
be that much of a problem anymore.
And this is, I think, could be feasible,but requires a lot of basic science work.

(21:45):
Because what we need to study now,and there are some ideas and some
data out there, is what are themechanisms that regulate this?
What is the mechanism thatregulates the ratio between
the toxic and a non-toxic one?
What's the specific about thenon-toxic ones and how could
you elevate that in cells?
And that is a biological mechanismthat has not been discovered.
But there are some ideas, and we havesome ideas of screenings that we could

(22:07):
set up, design certain screens to screenfor small molecules that could do that.
There's actually an, an antibiotic calledanoxycin that has been shown in mice,
not with Alzheimer, but with a ALS, amodel for ALS, to alleviate pretty much
all symptoms in two different models.
And this thing is known tostabilize microRNA, in our

(22:28):
book, protective microRNAs.
So there is already a drug outthere which was never screened for,
it was never designed to do that.
And I'm sure we can do better once we knowwhat'll we looking for, to design specific
screens, to get small molecules thatincrease the number of protective ones.
I think that would be my favoriteapproach because I think that may have
the least, side effects rather than,you know, playing with the toxic ones.

(22:51):
And that's the whole thing.
Treatment is one issue.
Prevention's another.
Obviously, the safety profile for anythingthat you want to use for prevention is
very different because you want peopleto take this for decades, so you
better have no side effects whatsoever.
But if you're in acute situation,like somebody has advanced cancer or
advanced Alzheimer's, you can have abeneficial effect with something it just

(23:14):
has a less favorable safety profile.
And so these are two different avenueswhich hopefully will be explored.
And we can't do this alone.
We are a small group.
We need the help of the community tobuy into this, start looking into that.
And some people that are waysmarter than us coming up with
ideas to make this happen.

So if you could wrap this up for me today, what
would you like people to knowabout your lab and what's next?

what's next in the cancer arena is that even though this
is, by design, a pan-cancer mechanism,that's not to say that there may not
be toxic RNA that are particularlyactive in one or another cancer.
So we need to get the full landscapeof what are the endogenous short RNAs.
As a basic scientist, I would like tocontinue to make discoveries in this

(24:01):
area and figure out how it's regulated.
That's the next big step and howit works to be able to use it in
a better way to treat diseases.
And of course, again,all depending on funding.
And opportunities.
We have no issue in venturingout into other diseases.
We did have a paper last year invirology on the first evidence how

(24:23):
viruses, in this case, h HIV onekills infected cells using the DICE
mechanism because if it's a billionyears old, it has to be everywhere.
And so obviously we area single, very small lab.
We cannot study everything,so we have to focus.

I understand.
You've also started a companyto help move this forward into
the translational science field.

the name of a company says it all, NUAgo, which is "NU" for
Northwest University or 'new' if you want.
And Ago is of course forChicago or for the key proteins.
They're called the AGO proteinsthat are part of this complex
that mediates RNA interference.
There you have it.
NUAgo is not specifically, it's inthe name, a cancer fighting company

(25:08):
only, but we'll see what happens.
We will be able to sponsor some of theresearch, at least initially in my lab
here at Northwestern through the companythat should start hopefully this year.
And then obviously, who knowswhere this will take us.

And I just have one more question.
What advice would you give to youngerinvestigators who are listening to this
and they're realizing, wow, you had toforge your own path and take a lot of
risk and maybe do things that weren'tthe popular thing to study or do.
What advice do you have for folks whothat may sound a little intimidating
to them, and what advice wouldyou give to a younger person just

(25:43):
starting off on this journey?

All depends on your level of risk tolerance, right?
So you have to develop something that isgrounded on what others are doing because
you always, as we say, standing on theshoulders of giants and you have to take
off from there, from their shoulders.
Then you really need to make sure that youmake a name, you carve out a niche, and
you make a career in order to get a grant,a federal grant, which is the only thing

(26:09):
that counts at institution like ours.
Don't find what proves your hypothesis.
Always try to disproveyour own hypothesis.
This thing started out byphenomena we couldn't explain.
And when I realized what it is, Ichallenged everybody in the lab.
Disprove me.
Show me that it is not true.
And every time we dove into further.
we found another mosaic piece thatfit into something that turned

(26:33):
into this whole concept, I thinkthat's the advice for young people.
Go your own way, but initiallyhave your bread and butter project.
Play safe.
Make a name.
Get the funding, but then,don't care about anybody.

Thank you Dr.
Peter for coming on the show.
You have some very excitingthings in the pipeline.
We'll continue to followalong, so thank you.

Thank you so much for having me.
This was fun.

Thanks for listening, and be sure to subscribe
to this show on Apple Podcasts orwherever you listen to podcasts.
And rate and review us alsofor medical professionals.
This episode of Breakthroughsis available for CME Credit.
Go to our website, feinbergnorthwestern edu, and search CME.

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