Molecular Mechanisms of Cancer

March 28, 2022

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March 27, 2022

Yale Cancer Center

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00:00Funding for Yale Cancer Answers is
00:02provided by Smilow Cancer Hospital.
00:06Welcome to Yale Cancer answers with your
00:09host doctor in East JGP are Yale Cancer
00:12answers features the latest information
00:13on cancer care by welcoming oncologists
00:16and specialists who are on the forefront
00:18of the battle to fight cancer this week.
00:21It's a conversation about the molecular
00:23mechanisms of cancer with Doctor Daryl Klein.
00:25Doctor Klein is an assistant professor of
00:28pharmacology at the Yale School of Medicine,
00:30where Doctor Chad Power as a
00:32professor of surgical oncology.
00:35So Darrell maybe we can start
00:36off by you telling us a little
00:38bit more about yourself and
00:40what it is exactly that you do.
00:42Yeah, I mean I think.
00:44My path to become a medical
00:47researcher involves my personal back
00:49story and my love of competition.
00:53In some ways, I feel like I've been
00:55destined to study kinases and cancer and
00:57their mechanisms and and with the hope of
01:01developing useful cancer therapeutics.
01:02And my career trajectory if you will.
01:05As a medical scientist,
01:07began long before my formal training.
01:10I grew up in New Jersey just outside
01:13of Philadelphia, and at a young age.
01:15My my sister was diagnosed with cancer.
01:18Kimberly, my sister, was diagnosed
01:21with MLE or chronic myeloid leukemia.
01:25It's a blood cancer that's rare
01:28in children at that time.
01:31Over 40 years ago now,
01:33Peter Noel at the University of
01:35Pennsylvania in Philadelphia was studying
01:38the driving mutations that lead to CML.
01:41And he discovered a chromosome alteration
01:43that he dubbed the Philadelphia
01:45chromosome and kmle patients,
01:47like my sister and and the results
01:50of that change.
01:51Is that a new protein is made a fusion
01:53of a tyrosine kinase signaling protein?
01:56That's that's stuck in the on position,
01:59and that instructs cells to.
02:01To divide and grow and thus cancer.
02:04And that protein became a target for
02:06drug discovery and it really heralded
02:08the era of precision medicine that
02:11is specifically targeting a single.
02:13You know bad protein with a drug and
02:15that and that was really exciting.
02:17And in 2001 there was this huge success with.
02:20The mat neighbor or Gleevec,
02:22and that became the first drug
02:25that was developed to target a
02:26specific kinase to treat a disease,
02:28and in this case, someone.
02:30And patients treated with this drug can
02:33live long lives with controlled disease.
02:36Unfortunately for you know, Kimberly,
02:39my sister, at that time it was.
02:40It was just the beginning of
02:43understanding this disease.
02:44And there were no therapeutics,
02:46and that meant you know,
02:47little could be done, and.
02:49In this powerlessness drives me to find
02:51ways to spare other families similar
02:53devastation and to better understand cancer.
02:57You know,
02:58I really have spent a large part of my career
03:00investigating the molecular basis for,
03:03for oncogenic signaling.
03:04And.
03:05You know on that path I attended
03:08the University of Pennsylvania
03:10for my undergrad in my PhD,
03:13and my medical degree,
03:14and I did clinical rotations at the
03:17Children's Hospital of Philadelphia Chop.
03:19So I was walking the same halls as Peter,
03:22Noel and my parents and my
03:25sister years before.
03:26I joined the MSTP or medical
03:29Scientist training program and.
03:31This was funded by the NIH,
03:33the National Institutes of Health,
03:35to grant to train a group of physicians,
03:38also to be researchers,
03:39and the goal of that program is
03:41basically to link basic science
03:43findings to the clinic.
03:45The bench to the bedside and to
03:48Brig lab progress into useful
03:51therapeutics as rapidly as possible.
03:53And I think the success of Leave Act was
03:56just the beginning of targeting kinases.
03:58These these tires and kinases
04:00other kinases and cancer.
04:02And so when I was at Penn,
04:04I studied under Professor Mark Lemon.
04:07He was working on those other kinases
04:09that lead to different cancers.
04:11And you know, to see how they might
04:14cause cancer and how we might leverage
04:17understanding their mechanisms
04:18to develop new therapeutics.
04:22I also mentioned you know my my
04:25desire for you know competition.
04:29And so one thing I I'm not sure
04:31that people really understand is
04:34how competitive research compete.
04:36And I, you know,
04:37I grew up playing sports in college
04:39and I love competing and and track and
04:41field and crew and football and baseball.
04:43And when I first joined Mark's
04:46lab at Penn and and was first
04:48introduced to lab research,
04:49I realized there that.
04:51Scientific researches is intensely
04:53competitive and I think it makes Olympic
04:56sport seem safe by comparison and and I
04:59love that and I loved everything about that.
05:03And then the problem is in
05:05sensually in science.
05:06You're competing with unknown
05:08competitors and and an unknown number
05:11of of teams and and the rules of the
05:14game are undefined and you don't even
05:16know when the conversation started.
05:18So,
05:18and certainly your competitors have
05:20more money and resources than you do,
05:22so you're always the underdog and and
05:25that excites me and I and I like that.
05:28You know an example.
05:29When we started the project will chat
05:31more about in a in a little bit.
05:33We were certain that that you know
05:35half a dozen other groups in the world
05:38were already working on it and and we
05:40didn't know how far along they were.
05:42And so all you know is what you don't know.
05:44And if you want to win,
05:46you have to work nonstop like 24/7.
05:48I once spent 50 hours straight in the lab
05:52when I was a grad student without sleeping.
05:54And then you know that was exciting to me.
05:57That's something you can't do in.
06:00In sport after the game you you go home,
06:03but science is a years long competition
06:06with no timeouts and and the
06:08intensity is is off the charts so.
06:12I think that that frames kind of.
06:14Why I became a medical researcher
06:17and and and why?
06:19Why I love doing the work that I do.
06:23So let's take a step back for a bit.
06:25I mean, that sounds really inspiring
06:28and and interesting in terms of
06:30how this kind of came full circle.
06:32How you? Had this experience
06:34with your sister and then went on
06:37to to become a scientist that's
06:39hopefully making a difference in the
06:41lives of other patients like her.
06:43But for our audience,
06:45maybe you can take a step back and
06:48tell us exactly like what is a kinase
06:51and why are they important in cancer?
06:54Sure, sure, yeah.
06:56I mean I should also mention
06:58that while I trained as A and
07:00MDP MD PhD physician scientist,
07:03I've actually chosen a path
07:06devoted entirely to research.
07:08So during training, when I you know,
07:11find myself engaging with patients
07:13and and talking to them about the
07:16unfortunately limited treatment options I,
07:17I found that difficult and frustrating
07:19and and all I wanted to do was rush
07:21back to the lab and and and find
07:24new potential therapeutic avenues.
07:25So I made a choice to devote
07:27myself entirely to lab work,
07:29but at the same time I'm still
07:31working with other physicians,
07:33scientists and clinicians to
07:34help bridge our our discoveries.
07:37To the bedside.
07:39Kinases are often drivers of
07:43cancers and and the one that I've
07:45been working on recently ALK and
07:48a plastic lymphoma kinases is a
07:50well known cancer related protein.
07:53And much like the protein involved
07:55in my sisters of Mle,
07:57it's a tyrosine kinase and
07:59basically tyrosine kinases instruct
08:01the cells to grow and divide,
08:04and if this is unregulated
08:07that leads to cancer.
08:10So ALK well, unlike the Siml case, ALK is.
08:15Is A is a receptor tyrosine kinase.
08:18So what that means is ALK is
08:20located in a different part of
08:22the cell than the CML kinase.
08:24So if it if a cell were an ocean,
08:27the CML kinase would be a submarine
08:30and ALK would be more like an aircraft
08:33carrier at the surface and so this.
08:36Localization difference has
08:38therapeutic implications.
08:39As you might imagine,
08:40you can't target a submarine the same
08:42way you would target in an aircraft carrier.
08:44So in the clinic we use small molecule.
08:47You know missile like drugs that can dive
08:49deep into the ocean to reach that kmle.
08:52Kinase submarine whereas for ALK we
08:54have an opportunity to use antibodies
08:57that can target it at the cell surface,
09:00so more like a.
09:01You know a B52 bomber.
09:05It's been known for years that
09:07ALK is a driver of neuroblastoma.
09:09Now neuroblastoma is a cancer of
09:12the peripheral nervous system.
09:15It's one of the more common pediatric
09:17cancers that accounts for more than
09:1910% of childhood cancer mortality.
09:23But clinically useful therapeutics
09:26have been slow to develop,
09:29and I think you know one of the key
09:32reasons for this slow development of
09:34treatments is likely the lack of a.
09:36Structural framework for the target alcc.
09:39Simply put,
09:40we have you know no idea what it
09:42looked like or how it functioned.
09:44It was a a complete mystery before our work.
09:47I mean the fact that ALK is expressed on
09:51neuroblastoma cells but is not present.
09:53On healthy tissue makes Alka
09:56veritable oncogenic beacon.
09:58That's a perfect target
10:01for precision medicine.
10:02It's much like the novel
10:04fusion protein and kmle.
10:06In each case the protein.
10:10Specifically,
10:10if you're targeting the protein specifically,
10:12it should have little side effects
10:14outside of the cancer itself.
10:16And the hope is that if we can target
10:19this kinase alken neuroblastoma.
10:22That we might have the same positive
10:25outcomes for neuroblastoma that
10:26we see for patients with KMLE.
10:29So you know one of the things that
10:32always fascinates me is how you
10:34find these things to begin with.
10:36I mean, how do we know that these
10:39kinases play a role in cancer?
10:41How does that? How do you figure that out?
10:44How do you know which kinases are
10:47submarines and which kinases are
10:49our aircraft carriers, I mean.
10:52And how did you figure out that
10:55these were important anyways?
10:57How does that happen?
11:00That's a good question.
11:01That's certainly outside
11:02of my lab's expertise.
11:07A lot of that is done through genomic
11:10work and associating certain genes
11:14with certain disease phenotypes,
11:17and so where my labs expertise
11:19comes in pretty much after the fact.
11:22Once these associations are known.
11:26That's where we come in to help define
11:29bio physically and structurally,
11:31exactly how these kinases
11:33and uncle genes are acting,
11:36and hopefully if we have a molecular
11:38picture of that how we might design
11:41and develop therapeutics to.
11:43To stall that and and prevent disease.
11:48So when you say that it it kind of all
11:51starts with understanding what genes
11:53are expressed in what genes aren't.
11:56I mean it, it sounds like the progress
11:59that we make in terms of cancer
12:03medicine is really investigators.
12:05Building on other investigators
12:07building on other investigators work.
12:10So somebody you know maybe was sequencing
12:12some genes and found that some genes were
12:16overexpressed in some cancers versus not.
12:19And then other people kind of discovered that
12:22that gene was associated with a protein like.
12:25A kinase and then you look at
12:28that kinase and say well where
12:30is it and how can we target it?
12:32Is that kind of how that works?
12:35That's
12:35exactly right, right? I mean,
12:37it's it's work of a tremendous number
12:40of individuals with differing expertise.
12:44Certainly the approach my lab takes
12:46is just one cog in that machine,
12:49one that's a bit further down,
12:51and probably less than the discovery stage.
12:52But one one that is keenly
12:55important to understand the
12:56mechanism of how molecules work,
12:59which can then give us insight
13:01into how we might target these
13:03and develop therapeutics.
13:04Around their function.
13:07And then the other question
13:09that that I often have is.
13:11OK, so you know you discover this kinase and
13:15you discover that it's important in cancer.
13:19Why is it that some kinases are important
13:22in some cancers but not in others?
13:25I mean, how do these kinases?
13:27Why? Why do you have these genes
13:30for these kinases to begin with?
13:33And why are they differentially expressed?
13:37Cancer often recapitulates the the paradigms
13:42that are important and during development.
13:47So all of these kinases are crucially
13:49important in the in the stages of development
13:53and help patterning and complex tissues.
13:56After that, they they often kind of
13:59are aren't used so much in adulthood,
14:02and it's only during cancer.
14:04In the the oncogenic process that a lot of
14:08these developmental pathways are reawakened,
14:12and they can be reawakened in different
14:14tissues and and different places,
14:16but they all.
14:17Lead to the same thing.
14:19Basically once you turn return
14:21a kinase on your turning on
14:24the the growth instructions and
14:27when that's not counterbalanced,
14:30that's how cancer develops.
14:33Well, we're going to take a
14:34short break for a medical minute,
14:36but when we come back,
14:38let's learn more about the molecular
14:40mechanisms of cancer and how exactly
14:43we target these differentially
14:44expressed kinases to actually
14:46make a difference for patients,
14:49please stay tuned for more with
14:51my guest doctor Daryl Klein
14:53funding for Yale Cancer Answers comes
14:55from Smilow Cancer Hospital with an
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16:13Welcome back to Yale Cancer answers.
16:15This is doctor in East Egg
16:16part and I'm joined tonight by
16:18my guest doctor, Daryl Klein.
16:19We're learning more about the molecular
16:22mechanisms of cancer and right before
16:24the break Daryl was telling us about
16:26this profoundly inspiring story of
16:28his sister who is diagnosed with CML,
16:30which really started his journey
16:32on becoming a physician scientist,
16:34and one who is particularly interested
16:37in these molecules called kinases,
16:41which really work.
16:43To activate the growth of of cancer
16:48cells and so you know Darrell before
16:51the break you were mentioning that
16:54eurolab really after we know that
16:57you know a kinase is involved in a
17:00particular cancer is really involved
17:03in looking at its its structure
17:06and kind of how to target it.
17:08Is that right?
17:10Exactly,
17:12my lab is a structural biology lab,
17:15so you know, we're sensually photographers.
17:18But we take pictures of of very,
17:20very tiny things, molecules and proteins,
17:24and so this. Requires specialized
17:26equipment cameras if you will.
17:28That use X rays and electrons rather
17:32than light in the in the visual
17:35spectrum that that we're used to.
17:37Uhm? You know, many people know.
17:40DNA, so let's start there.
17:42People have heard of DNA and Watson
17:45and Crick and and they're double Helix.
17:48And DNA is is basically a cookbook
17:51with 10s of thousands of recipes,
17:54and they're mostly protein recipes,
17:57so I guess it's a keto or Paleo cookbook.
18:02ALK is one of these recipes.
18:05And the recipe in the DNA cookbook tells us
18:08the ingredients and the order to make alcc.
18:12But one big problem with this DNA cookbook.
18:17Is it's not illustrated,
18:18so we have no idea what the
18:21final product will look like.
18:23So you know my lab follows the recipe to
18:26take pictures of the final products to.
18:29To illustrate this, this DNA cookbook.
18:32So we take molecular photographs
18:35of the protein and also the mutants
18:39that are found in cancer.
18:41And in these pictures give us a better
18:44understanding of of how things supposed
18:46to look like and how it changes in cancer.
18:49And in this can inform us
18:52about approaches to.
18:53Designing targeted therapeutics.
18:58So my lab just reported the structure
19:01of of the protein ALK in nature.
19:05That's the tyrosine kinase that's
19:08important in neuroblastoma.
19:10And this gave us a first look at
19:13this unique uncle Gene and it's,
19:16you know it's going to be impossible
19:18for me to relay the complexities here.
19:21But if we stick to our.
19:23Analogy of the the cell is an ocean, it's.
19:26It's not unreasonable to say that
19:28Alcc did actually look a bit like an
19:31aircraft carrier. I mean it had this.
19:34Unusual a long gated structure and it
19:37probably lies parallel to the to the surface,
19:41so it's like an aircraft carrier
19:43floating on the water.
19:44Or the surface of a cell.
19:47And and furthermore,
19:48we can see how it actually gets activated.
19:52Basically two of these aircraft carriers
19:55line up next to one another and in
19:58that position they're then capable to
20:00sell to send their their growth signals,
20:03which ultimately end up being
20:05cancerous growth signals.
20:06To the neuroblastoma cell.
20:09Uncontrolled ALK activation like
20:11this leads to cancer and it and it
20:14results from the tumor continuing to
20:16express this developmental out gene
20:19along with its stimulatory ligand.
20:24Our research reveals an approach
20:26to shutting off ALK and and that
20:29it can be quite straightforward.
20:31Potentially if we use our structure
20:35as a as a blueprint,
20:36we can see clear areas where
20:38we would want to target this.
20:40This aircraft like molecule.
20:41I mean there's certain vulnerabilities
20:44that are revealed in the structure that
20:46we can strategically target and and
20:48you know sync this aircraft carrier,
20:50and so my lab now is designing potent
20:53antibodies. That specifically
20:55target these regions in ALK,
20:58and you know there's there's small
21:00molecules currently out there in use for.
21:02Neuroblastoma, as well as many other
21:05different cancers that are driven or
21:07or partially dependent on on kinases.
21:11And compared to small molecule
21:13therapeutics antibodies,
21:14I think can offer a great benefit.
21:17The small molecule drugs that
21:19are now currently in use like
21:22prison and and learn Latin.
21:24They target the intracellular.
21:25The actual kinase domain of the protein out.
21:29And one problem with these types of
21:32inhibitors is that you can't keep
21:34fooling the cancer for very long.
21:35They the cancer figures out this
21:37trip quite fast that you're trying
21:39to inhibit it in this in this domain,
21:42and they and the cancer makes changes
21:45that diminish the drugs impact.
21:47Whereas I think the antibody
21:49approach is is is a more brute
21:52force approach and it's harder for
21:54the cancer to overcome this,
21:55the strategy of inhibition.
21:57I think the the therapeutic future
22:00will likely use a combination
22:02of these two to completely.
22:05Dismantle the the out machinery.
22:09In some ways you know cancer can be
22:11feod viewed as having some of the
22:13similar challenges that we see for SARS,
22:15Co V2 and both use similar
22:18strategies to overcome disease.
22:20Both you know cancer and
22:23viruses mutate rapidly.
22:25And they can evolve to
22:28different inhibitor approaches.
22:30And just as we use antibodies
22:32through vaccination or or directly
22:35injecting recombinant antibodies and
22:38small molecules to overcome COVID.
22:41Now we have a new blueprint for ALK to
22:44help us overcome similar challenges
22:46that are encountered in in cancer
22:49and in particular neuroblastoma.
22:52And it sounds like when you know the the
22:55structure of these aircraft carriers.
22:58But you can be very specific about
23:00you know targeting those particular
23:03molecules as opposed to normal cells.
23:06So you might have you know
23:08a bomber that only targets,
23:11you know that flatbed where the
23:13aircraft lands on the aircraft carrier.
23:15Or you can have some sort of a.
23:19A mechanism whereby these two aircraft
23:22carriers can't line up together that really
23:25wouldn't apply in any other situation,
23:27so you can try to get more precise
23:30or more targeted therapies.
23:32Is that right?
23:34That's exactly right,
23:35and remember that I said that you know,
23:38since alpha is expressed only
23:40on neuroblastoma cells but not
23:42present on healthy tissue,
23:44it really makes targeting
23:46ALK the perfect for you know.
23:48Set up for precision medicine
23:49and then a layer on top of that,
23:52which I think you were just referring
23:54to is now that we know the detailed
23:57structure and blueprints of this.
23:59And that's exactly what we're trying to do.
24:00We're trying to design
24:02antibodies that specifically.
24:04Block areas on the protein that are
24:07involved in important for it's activation.
24:10That is precisely where the ligand
24:13binds to activate the receptor and
24:17getting back to how it's activated.
24:20Where we see the the two molecules
24:23lining up side-by-side to each other,
24:25we're designing antibodies that can
24:27block that interface to prevent it
24:30from being activated that is being
24:32activated independent of ligand.
24:34Which could be caused by certain mutations,
24:36which is further research that we're
24:39doing now or or with the ligand.
24:42So we're using all this information
24:45to specifically design antibodies
24:48that are tailored to this molecule
24:50and the and the type of mutations
24:53or mechanisms that activate it
24:56specifically in in neuroblastoma.
25:00And so as you design these
25:02antibodies in these treatments,
25:04you're doing that in the lab. How?
25:07How does it actually get into patients?
25:09How does it affect people like your sister?
25:12Because that's where the story
25:14really started and how long
25:16does that whole process take?
25:20You're right, that's a that's certainly
25:22is is a long process and you know
25:24Cancer Research is is so matured and
25:27specialized now that it really requires
25:29you know effort to put these discoveries
25:32into usable formats and for others
25:34to build upon and meaningful ways.
25:37And just as the NIH created that MSTP
25:40program to link basic science and patient
25:43Care now I think we need similar links
25:45between basic science researchers.
25:47I mean, the you know RNA biologist
25:51and chromosome researcher and.
25:52And in the biophysicist like me
25:54trying to link up with the model
25:57Organism biologist to test the a lot
25:59of these and preclinical setups.
26:02We all speak a different scientific dialect
26:04and we have different perspectives,
26:06so you know how do we work together
26:11and in one answer to that is is,
26:13you know being part of the Yale Cancer
26:15Biol Biology Institute that I'm a part of.
26:17You know we we really bring
26:20together desperate researchers among
26:22those interested in cancer.
26:24And so you know now I have and and
26:26being a physician scientist so you know
26:29now there's a cohort of people and
26:32colleagues that I can work with that
26:35can bring our developing antibodies
26:37that we have into preclinical testing
26:40quite rapidly to see if they do.
26:44So good activity in vivo and then that
26:48hopefully can be rapidly leveraged
26:50into reaching the the patients that
26:53desperately need these treatments.
26:57Sounds very much like you
26:58had mentioned earlier,
27:00but this is kind of a microcosm for
27:02the macrocosm of how science works,
27:05that that your lab puts together.
27:07People who all kind of come at
27:09the problem of of ALK from a
27:12slightly different vantage point.
27:14But the work in your lab kind of builds
27:18on the work of other people's labs,
27:20and so maybe in in the last
27:23few minutes that we have,
27:25you could tell us kind of a little bit about.
27:27How that works in the grand scheme of things?
27:29I mean, it sounds like.
27:31One of the things that we've realized with
27:33the pandemic is that the world is shrinking,
27:35and hopefully the scientific discovery
27:38from one lab to another kind of.
27:42Bounces around fairly easily.
27:43How does that collaboration work?
27:46I think it is. It is certainly a challenge
27:49and I think you know getting getting
27:52researchers to to talk to each other and
27:55work together is an important part of that.
27:58And like you said, I think you know
28:01during the pandemic and having people
28:04communicate in different ways like we
28:06are now through zoom and other things.
28:09Maybe the world is shrinking a bit and I
28:11think that's a good thing for science and
28:14that's a good thing for research because.
28:17Of course, all of us working
28:19independently and making advances.
28:21We don't want them to go unnoticed
28:23by the people next in that chain
28:25that you were talking about.
28:26That's necessary to make the
28:28leap to bring these discoveries
28:31to their therapeutic potential.
28:33Doctor Daryl Klein is an assistant
28:36professor of pharmacology at
28:37the Yale School of Medicine.
28:39If you have questions,
28:41the address is canceranswers@yale.edu
28:43and past editions of the program
28:45are available in audio and written.
28:47Farm at yalecancercenter.org.
28:49We hope you'll join us next week to
28:52learn more about the fight against
28:53cancer here on Connecticut Public
28:55radio funding for Yale Cancer Answers
28:57is provided by Smilow Cancer Hospital.