Molecular Mechanisms of Cancer

Transcript

00:00 --> 00:02Funding for Yale Cancer Answers is
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00:06 --> 00:08Welcome to Yale Cancer answers with your
00:08 --> 00:11host doctor in East JGP are Yale Cancer
00:11 --> 00:13answers features the latest information
00:13 --> 00:15on cancer care by welcoming oncologists
00:15 --> 00:18and specialists who are on the forefront
00:18 --> 00:20of the battle to fight cancer this week.
00:20 --> 00:22It's a conversation about the molecular
00:22 --> 00:25mechanisms of cancer with Doctor Daryl Klein.
00:25 --> 00:27Doctor Klein is an assistant professor of
00:27 --> 00:30pharmacology at the Yale School of Medicine,
00:30 --> 00:32where Doctor Chad Power as a
00:32 --> 00:33professor of surgical oncology.
00:34 --> 00:36So Darrell maybe we can start
00:36 --> 00:38off by you telling us a little
00:38 --> 00:39bit more about yourself and
00:39 --> 00:41what it is exactly that you do.
00:42 --> 00:43Yeah, I mean I think.
00:43 --> 00:46My path to become a medical
00:46 --> 00:49researcher involves my personal back
00:49 --> 00:52story and my love of competition.
00:52 --> 00:54In some ways, I feel like I've been
00:54 --> 00:57destined to study kinases and cancer and
00:57 --> 01:00their mechanisms and and with the hope of
01:00 --> 01:02developing useful cancer therapeutics.
01:02 --> 01:05And my career trajectory if you will.
01:05 --> 01:06As a medical scientist,
01:06 --> 01:10began long before my formal training.
01:10 --> 01:12I grew up in New Jersey just outside
01:12 --> 01:14of Philadelphia, and at a young age.
01:14 --> 01:18My my sister was diagnosed with cancer.
01:18 --> 01:21Kimberly, my sister, was diagnosed
01:21 --> 01:25with MLE or chronic myeloid leukemia.
01:25 --> 01:28It's a blood cancer that's rare
01:28 --> 01:30in children at that time.
01:30 --> 01:32Over 40 years ago now,
01:32 --> 01:35Peter Noel at the University of
01:35 --> 01:37Pennsylvania in Philadelphia was studying
01:37 --> 01:40the driving mutations that lead to CML.
01:40 --> 01:43And he discovered a chromosome alteration
01:43 --> 01:45that he dubbed the Philadelphia
01:45 --> 01:47chromosome and kmle patients,
01:47 --> 01:49like my sister and and the results
01:49 --> 01:50of that change.
01:50 --> 01:53Is that a new protein is made a fusion
01:53 --> 01:56of a tyrosine kinase signaling protein?
01:56 --> 01:58That's that's stuck in the on position,
01:58 --> 02:00and that instructs cells to.
02:00 --> 02:03To divide and grow and thus cancer.
02:03 --> 02:06And that protein became a target for
02:06 --> 02:08drug discovery and it really heralded
02:08 --> 02:10the era of precision medicine that
02:10 --> 02:12is specifically targeting a single.
02:12 --> 02:15You know bad protein with a drug and
02:15 --> 02:17that and that was really exciting.
02:17 --> 02:20And in 2001 there was this huge success with.
02:20 --> 02:22The mat neighbor or Gleevec,
02:22 --> 02:24and that became the first drug
02:24 --> 02:26that was developed to target a
02:26 --> 02:28specific kinase to treat a disease,
02:28 --> 02:30and in this case, someone.
02:30 --> 02:33And patients treated with this drug can
02:33 --> 02:36live long lives with controlled disease.
02:36 --> 02:38Unfortunately for you know, Kimberly,
02:38 --> 02:40my sister, at that time it was.
02:40 --> 02:42It was just the beginning of
02:42 --> 02:44understanding this disease.
02:44 --> 02:45And there were no therapeutics,
02:45 --> 02:46and that meant you know,
02:46 --> 02:48little could be done, and.
02:48 --> 02:50In this powerlessness drives me to find
02:50 --> 02:53ways to spare other families similar
02:53 --> 02:57devastation and to better understand cancer.
02:57 --> 02:57You know,
02:57 --> 03:00I really have spent a large part of my career
03:00 --> 03:02investigating the molecular basis for,
03:02 --> 03:04for oncogenic signaling.
03:04 --> 03:04And.
03:04 --> 03:07You know on that path I attended
03:07 --> 03:10the University of Pennsylvania
03:10 --> 03:12for my undergrad in my PhD,
03:12 --> 03:13and my medical degree,
03:13 --> 03:16and I did clinical rotations at the
03:16 --> 03:19Children's Hospital of Philadelphia Chop.
03:19 --> 03:21So I was walking the same halls as Peter,
03:21 --> 03:24Noel and my parents and my
03:24 --> 03:25sister years before.
03:26 --> 03:29I joined the MSTP or medical
03:29 --> 03:31Scientist training program and.
03:31 --> 03:33This was funded by the NIH,
03:33 --> 03:35the National Institutes of Health,
03:35 --> 03:37to grant to train a group of physicians,
03:37 --> 03:39also to be researchers,
03:39 --> 03:41and the goal of that program is
03:41 --> 03:43basically to link basic science
03:43 --> 03:45findings to the clinic.
03:45 --> 03:48The bench to the bedside and to
03:48 --> 03:50Brig lab progress into useful
03:50 --> 03:52therapeutics as rapidly as possible.
03:52 --> 03:56And I think the success of Leave Act was
03:56 --> 03:58just the beginning of targeting kinases.
03:58 --> 04:00These these tires and kinases
04:00 --> 04:02other kinases and cancer.
04:02 --> 04:03And so when I was at Penn,
04:03 --> 04:06I studied under Professor Mark Lemon.
04:06 --> 04:09He was working on those other kinases
04:09 --> 04:11that lead to different cancers.
04:11 --> 04:14And you know, to see how they might
04:14 --> 04:16cause cancer and how we might leverage
04:16 --> 04:18understanding their mechanisms
04:18 --> 04:21to develop new therapeutics.
04:21 --> 04:24I also mentioned you know my my
04:24 --> 04:28desire for you know competition.
04:28 --> 04:31And so one thing I I'm not sure
04:31 --> 04:33that people really understand is
04:33 --> 04:35how competitive research compete.
04:35 --> 04:36And I, you know,
04:36 --> 04:38I grew up playing sports in college
04:38 --> 04:40and I love competing and and track and
04:40 --> 04:43field and crew and football and baseball.
04:43 --> 04:46And when I first joined Mark's
04:46 --> 04:48lab at Penn and and was first
04:48 --> 04:49introduced to lab research,
04:49 --> 04:51I realized there that.
04:51 --> 04:53Scientific researches is intensely
04:53 --> 04:56competitive and I think it makes Olympic
04:56 --> 04:59sport seem safe by comparison and and I
04:59 --> 05:02love that and I loved everything about that.
05:02 --> 05:04And then the problem is in
05:04 --> 05:06sensually in science.
05:06 --> 05:08You're competing with unknown
05:08 --> 05:11competitors and and an unknown number
05:11 --> 05:13of of teams and and the rules of the
05:13 --> 05:15game are undefined and you don't even
05:15 --> 05:17know when the conversation started.
05:17 --> 05:18So,
05:18 --> 05:20and certainly your competitors have
05:20 --> 05:22more money and resources than you do,
05:22 --> 05:25so you're always the underdog and and
05:25 --> 05:28that excites me and I and I like that.
05:28 --> 05:29You know an example.
05:29 --> 05:31When we started the project will chat
05:31 --> 05:33more about in a in a little bit.
05:33 --> 05:35We were certain that that you know
05:35 --> 05:37half a dozen other groups in the world
05:37 --> 05:40were already working on it and and we
05:40 --> 05:42didn't know how far along they were.
05:42 --> 05:44And so all you know is what you don't know.
05:44 --> 05:45And if you want to win,
05:45 --> 05:48you have to work nonstop like 24/7.
05:48 --> 05:51I once spent 50 hours straight in the lab
05:51 --> 05:54when I was a grad student without sleeping.
05:54 --> 05:57And then you know that was exciting to me.
05:57 --> 05:59That's something you can't do in.
05:59 --> 06:02In sport after the game you you go home,
06:02 --> 06:05but science is a years long competition
06:05 --> 06:08with no timeouts and and the
06:08 --> 06:11intensity is is off the charts so.
06:11 --> 06:14I think that that frames kind of.
06:14 --> 06:16Why I became a medical researcher
06:16 --> 06:18and and and why?
06:18 --> 06:21Why I love doing the work that I do.
06:22 --> 06:25So let's take a step back for a bit.
06:25 --> 06:27I mean, that sounds really inspiring
06:27 --> 06:30and and interesting in terms of
06:30 --> 06:32how this kind of came full circle.
06:32 --> 06:34How you? Had this experience
06:34 --> 06:36with your sister and then went on
06:36 --> 06:38to to become a scientist that's
06:38 --> 06:41hopefully making a difference in the
06:41 --> 06:43lives of other patients like her.
06:43 --> 06:44But for our audience,
06:44 --> 06:47maybe you can take a step back and
06:47 --> 06:50tell us exactly like what is a kinase
06:50 --> 06:53and why are they important in cancer?
06:54 --> 06:55Sure, sure, yeah.
06:55 --> 06:57I mean I should also mention
06:57 --> 07:00that while I trained as A and
07:00 --> 07:02MDP MD PhD physician scientist,
07:02 --> 07:05I've actually chosen a path
07:05 --> 07:08devoted entirely to research.
07:08 --> 07:11So during training, when I you know,
07:11 --> 07:12find myself engaging with patients
07:12 --> 07:15and and talking to them about the
07:15 --> 07:17unfortunately limited treatment options I,
07:17 --> 07:19I found that difficult and frustrating
07:19 --> 07:21and and all I wanted to do was rush
07:21 --> 07:23back to the lab and and and find
07:23 --> 07:25new potential therapeutic avenues.
07:25 --> 07:27So I made a choice to devote
07:27 --> 07:29myself entirely to lab work,
07:29 --> 07:31but at the same time I'm still
07:31 --> 07:32working with other physicians,
07:32 --> 07:34scientists and clinicians to
07:34 --> 07:36help bridge our our discoveries.
07:36 --> 07:39To the bedside.
07:39 --> 07:42Kinases are often drivers of
07:42 --> 07:45cancers and and the one that I've
07:45 --> 07:47been working on recently ALK and
07:47 --> 07:50a plastic lymphoma kinases is a
07:50 --> 07:53well known cancer related protein.
07:53 --> 07:55And much like the protein involved
07:55 --> 07:56in my sisters of Mle,
07:56 --> 07:59it's a tyrosine kinase and
07:59 --> 08:01basically tyrosine kinases instruct
08:01 --> 08:04the cells to grow and divide,
08:04 --> 08:07and if this is unregulated
08:07 --> 08:09that leads to cancer.
08:09 --> 08:15So ALK well, unlike the Siml case, ALK is.
08:15 --> 08:18Is A is a receptor tyrosine kinase.
08:18 --> 08:19So what that means is ALK is
08:19 --> 08:21located in a different part of
08:21 --> 08:24the cell than the CML kinase.
08:24 --> 08:27So if it if a cell were an ocean,
08:27 --> 08:29the CML kinase would be a submarine
08:29 --> 08:32and ALK would be more like an aircraft
08:32 --> 08:35carrier at the surface and so this.
08:35 --> 08:37Localization difference has
08:37 --> 08:38therapeutic implications.
08:38 --> 08:40As you might imagine,
08:40 --> 08:42you can't target a submarine the same
08:42 --> 08:44way you would target in an aircraft carrier.
08:44 --> 08:46So in the clinic we use small molecule.
08:46 --> 08:49You know missile like drugs that can dive
08:49 --> 08:51deep into the ocean to reach that kmle.
08:51 --> 08:54Kinase submarine whereas for ALK we
08:54 --> 08:56have an opportunity to use antibodies
08:56 --> 08:59that can target it at the cell surface,
08:59 --> 09:01so more like a.
09:01 --> 09:05You know a B52 bomber.
09:05 --> 09:06It's been known for years that
09:06 --> 09:09ALK is a driver of neuroblastoma.
09:09 --> 09:12Now neuroblastoma is a cancer of
09:12 --> 09:14the peripheral nervous system.
09:14 --> 09:17It's one of the more common pediatric
09:17 --> 09:19cancers that accounts for more than
09:19 --> 09:2310% of childhood cancer mortality.
09:23 --> 09:26But clinically useful therapeutics
09:26 --> 09:29have been slow to develop,
09:29 --> 09:32and I think you know one of the key
09:32 --> 09:33reasons for this slow development of
09:33 --> 09:36treatments is likely the lack of a.
09:36 --> 09:39Structural framework for the target alcc.
09:39 --> 09:39Simply put,
09:39 --> 09:41we have you know no idea what it
09:41 --> 09:43looked like or how it functioned.
09:43 --> 09:47It was a a complete mystery before our work.
09:47 --> 09:50I mean the fact that ALK is expressed on
09:50 --> 09:53neuroblastoma cells but is not present.
09:53 --> 09:56On healthy tissue makes Alka
09:56 --> 09:58veritable oncogenic beacon.
09:58 --> 10:00That's a perfect target
10:00 --> 10:02for precision medicine.
10:02 --> 10:04It's much like the novel
10:04 --> 10:05fusion protein and kmle.
10:05 --> 10:09In each case the protein.
10:09 --> 10:10Specifically,
10:10 --> 10:12if you're targeting the protein specifically,
10:12 --> 10:14it should have little side effects
10:14 --> 10:16outside of the cancer itself.
10:16 --> 10:19And the hope is that if we can target
10:19 --> 10:21this kinase alken neuroblastoma.
10:21 --> 10:24That we might have the same positive
10:24 --> 10:26outcomes for neuroblastoma that
10:26 --> 10:27we see for patients with KMLE.
10:29 --> 10:32So you know one of the things that
10:32 --> 10:34always fascinates me is how you
10:34 --> 10:35find these things to begin with.
10:35 --> 10:39I mean, how do we know that these
10:39 --> 10:41kinases play a role in cancer?
10:41 --> 10:43How does that? How do you figure that out?
10:43 --> 10:46How do you know which kinases are
10:46 --> 10:49submarines and which kinases are
10:49 --> 10:51our aircraft carriers, I mean.
10:51 --> 10:54And how did you figure out that
10:54 --> 10:56these were important anyways?
10:56 --> 10:57How does that happen?
10:59 --> 11:01That's a good question.
11:01 --> 11:02That's certainly outside
11:02 --> 11:06of my lab's expertise.
11:06 --> 11:10A lot of that is done through genomic
11:10 --> 11:13work and associating certain genes
11:13 --> 11:16with certain disease phenotypes,
11:16 --> 11:19and so where my labs expertise
11:19 --> 11:21comes in pretty much after the fact.
11:21 --> 11:25Once these associations are known.
11:25 --> 11:28That's where we come in to help define
11:28 --> 11:30bio physically and structurally,
11:30 --> 11:32exactly how these kinases
11:32 --> 11:35and uncle genes are acting,
11:35 --> 11:37and hopefully if we have a molecular
11:37 --> 11:40picture of that how we might design
11:40 --> 11:42and develop therapeutics to.
11:42 --> 11:46To stall that and and prevent disease.
11:47 --> 11:50So when you say that it it kind of all
11:50 --> 11:53starts with understanding what genes
11:53 --> 11:56are expressed in what genes aren't.
11:56 --> 11:59I mean it, it sounds like the progress
11:59 --> 12:02that we make in terms of cancer
12:02 --> 12:04medicine is really investigators.
12:04 --> 12:06Building on other investigators
12:06 --> 12:09building on other investigators work.
12:09 --> 12:12So somebody you know maybe was sequencing
12:12 --> 12:16some genes and found that some genes were
12:16 --> 12:18overexpressed in some cancers versus not.
12:18 --> 12:21And then other people kind of discovered that
12:21 --> 12:25that gene was associated with a protein like.
12:25 --> 12:27A kinase and then you look at
12:27 --> 12:29that kinase and say well where
12:29 --> 12:32is it and how can we target it?
12:32 --> 12:34Is that kind of how that works?
12:34 --> 12:34That's
12:34 --> 12:36exactly right, right? I mean,
12:36 --> 12:40it's it's work of a tremendous number
12:40 --> 12:43of individuals with differing expertise.
12:43 --> 12:46Certainly the approach my lab takes
12:46 --> 12:49is just one cog in that machine,
12:49 --> 12:50one that's a bit further down,
12:50 --> 12:52and probably less than the discovery stage.
12:52 --> 12:54But one one that is keenly
12:54 --> 12:56important to understand the
12:56 --> 12:58mechanism of how molecules work,
12:58 --> 13:00which can then give us insight
13:00 --> 13:02into how we might target these
13:02 --> 13:04and develop therapeutics.
13:04 --> 13:05Around their function.
13:06 --> 13:08And then the other question
13:08 --> 13:11that that I often have is.
13:11 --> 13:14OK, so you know you discover this kinase and
13:14 --> 13:18you discover that it's important in cancer.
13:18 --> 13:22Why is it that some kinases are important
13:22 --> 13:25in some cancers but not in others?
13:25 --> 13:27I mean, how do these kinases?
13:27 --> 13:30Why? Why do you have these genes
13:30 --> 13:33for these kinases to begin with?
13:33 --> 13:36And why are they differentially expressed?
13:37 --> 13:41Cancer often recapitulates the the paradigms
13:41 --> 13:46that are important and during development.
13:46 --> 13:49So all of these kinases are crucially
13:49 --> 13:52important in the in the stages of development
13:52 --> 13:55and help patterning and complex tissues.
13:55 --> 13:58After that, they they often kind of
13:58 --> 14:01are aren't used so much in adulthood,
14:01 --> 14:04and it's only during cancer.
14:04 --> 14:07In the the oncogenic process that a lot of
14:07 --> 14:11these developmental pathways are reawakened,
14:11 --> 14:14and they can be reawakened in different
14:14 --> 14:16tissues and and different places,
14:16 --> 14:17but they all.
14:17 --> 14:18Lead to the same thing.
14:18 --> 14:20Basically once you turn return
14:20 --> 14:24a kinase on your turning on
14:24 --> 14:27the the growth instructions and
14:27 --> 14:30when that's not counterbalanced,
14:30 --> 14:31that's how cancer develops.
14:32 --> 14:34Well, we're going to take a
14:34 --> 14:36short break for a medical minute,
14:36 --> 14:37but when we come back,
14:37 --> 14:40let's learn more about the molecular
14:40 --> 14:42mechanisms of cancer and how exactly
14:42 --> 14:44we target these differentially
14:44 --> 14:46expressed kinases to actually
14:46 --> 14:49make a difference for patients,
14:49 --> 14:50please stay tuned for more with
14:50 --> 14:52my guest doctor Daryl Klein
14:53 --> 14:55funding for Yale Cancer Answers comes
14:55 --> 14:57from Smilow Cancer Hospital with an
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16:13 --> 16:15Welcome back to Yale Cancer answers.
16:15 --> 16:16This is doctor in East Egg
16:16 --> 16:17part and I'm joined tonight by
16:17 --> 16:19my guest doctor, Daryl Klein.
16:19 --> 16:21We're learning more about the molecular
16:21 --> 16:23mechanisms of cancer and right before
16:23 --> 16:25the break Daryl was telling us about
16:25 --> 16:27this profoundly inspiring story of
16:27 --> 16:30his sister who is diagnosed with CML,
16:30 --> 16:32which really started his journey
16:32 --> 16:34on becoming a physician scientist,
16:34 --> 16:37and one who is particularly interested
16:37 --> 16:41in these molecules called kinases,
16:41 --> 16:43which really work.
16:43 --> 16:48To activate the growth of of cancer
16:48 --> 16:51cells and so you know Darrell before
16:51 --> 16:53the break you were mentioning that
16:53 --> 16:56eurolab really after we know that
16:56 --> 17:00you know a kinase is involved in a
17:00 --> 17:02particular cancer is really involved
17:02 --> 17:05in looking at its its structure
17:05 --> 17:08and kind of how to target it.
17:08 --> 17:09Is that right?
17:09 --> 17:10Exactly,
17:11 --> 17:14my lab is a structural biology lab,
17:14 --> 17:18so you know, we're sensually photographers.
17:18 --> 17:20But we take pictures of of very,
17:20 --> 17:23very tiny things, molecules and proteins,
17:23 --> 17:26and so this. Requires specialized
17:26 --> 17:28equipment cameras if you will.
17:28 --> 17:32That use X rays and electrons rather
17:32 --> 17:34than light in the in the visual
17:34 --> 17:36spectrum that that we're used to.
17:36 --> 17:39Uhm? You know, many people know.
17:39 --> 17:41DNA, so let's start there.
17:41 --> 17:44People have heard of DNA and Watson
17:44 --> 17:48and Crick and and they're double Helix.
17:48 --> 17:51And DNA is is basically a cookbook
17:51 --> 17:54with 10s of thousands of recipes,
17:54 --> 17:57and they're mostly protein recipes,
17:57 --> 18:01so I guess it's a keto or Paleo cookbook.
18:01 --> 18:04ALK is one of these recipes.
18:04 --> 18:08And the recipe in the DNA cookbook tells us
18:08 --> 18:12the ingredients and the order to make alcc.
18:12 --> 18:16But one big problem with this DNA cookbook.
18:16 --> 18:18Is it's not illustrated,
18:18 --> 18:20so we have no idea what the
18:20 --> 18:22final product will look like.
18:22 --> 18:25So you know my lab follows the recipe to
18:25 --> 18:28take pictures of the final products to.
18:28 --> 18:32To illustrate this, this DNA cookbook.
18:32 --> 18:35So we take molecular photographs
18:35 --> 18:38of the protein and also the mutants
18:38 --> 18:40that are found in cancer.
18:40 --> 18:44And in these pictures give us a better
18:44 --> 18:46understanding of of how things supposed
18:46 --> 18:49to look like and how it changes in cancer.
18:49 --> 18:51And in this can inform us
18:51 --> 18:53about approaches to.
18:53 --> 18:57Designing targeted therapeutics.
18:57 --> 19:01So my lab just reported the structure
19:01 --> 19:05of of the protein ALK in nature.
19:05 --> 19:08That's the tyrosine kinase that's
19:08 --> 19:10important in neuroblastoma.
19:10 --> 19:12And this gave us a first look at
19:12 --> 19:15this unique uncle Gene and it's,
19:15 --> 19:18you know it's going to be impossible
19:18 --> 19:21for me to relay the complexities here.
19:21 --> 19:23But if we stick to our.
19:23 --> 19:25Analogy of the the cell is an ocean, it's.
19:25 --> 19:28It's not unreasonable to say that
19:28 --> 19:30Alcc did actually look a bit like an
19:30 --> 19:33aircraft carrier. I mean it had this.
19:33 --> 19:37Unusual a long gated structure and it
19:37 --> 19:40probably lies parallel to the to the surface,
19:40 --> 19:42so it's like an aircraft carrier
19:42 --> 19:44floating on the water.
19:44 --> 19:46Or the surface of a cell.
19:46 --> 19:48And and furthermore,
19:48 --> 19:52we can see how it actually gets activated.
19:52 --> 19:54Basically two of these aircraft carriers
19:54 --> 19:57line up next to one another and in
19:57 --> 20:00that position they're then capable to
20:00 --> 20:02sell to send their their growth signals,
20:02 --> 20:05which ultimately end up being
20:05 --> 20:06cancerous growth signals.
20:06 --> 20:08To the neuroblastoma cell.
20:08 --> 20:10Uncontrolled ALK activation like
20:10 --> 20:13this leads to cancer and it and it
20:13 --> 20:16results from the tumor continuing to
20:16 --> 20:18express this developmental out gene
20:18 --> 20:23along with its stimulatory ligand.
20:23 --> 20:26Our research reveals an approach
20:26 --> 20:29to shutting off ALK and and that
20:29 --> 20:31it can be quite straightforward.
20:31 --> 20:34Potentially if we use our structure
20:34 --> 20:35as a as a blueprint,
20:35 --> 20:37we can see clear areas where
20:37 --> 20:39we would want to target this.
20:39 --> 20:41This aircraft like molecule.
20:41 --> 20:43I mean there's certain vulnerabilities
20:43 --> 20:46that are revealed in the structure that
20:46 --> 20:48we can strategically target and and
20:48 --> 20:50you know sync this aircraft carrier,
20:50 --> 20:53and so my lab now is designing potent
20:53 --> 20:54antibodies. That specifically
20:54 --> 20:57target these regions in ALK,
20:57 --> 21:00and you know there's there's small
21:00 --> 21:02molecules currently out there in use for.
21:02 --> 21:04Neuroblastoma, as well as many other
21:04 --> 21:07different cancers that are driven or
21:07 --> 21:10or partially dependent on on kinases.
21:10 --> 21:12And compared to small molecule
21:12 --> 21:13therapeutics antibodies,
21:13 --> 21:16I think can offer a great benefit.
21:16 --> 21:18The small molecule drugs that
21:18 --> 21:21are now currently in use like
21:21 --> 21:23prison and and learn Latin.
21:23 --> 21:25They target the intracellular.
21:25 --> 21:29The actual kinase domain of the protein out.
21:29 --> 21:31And one problem with these types of
21:31 --> 21:33inhibitors is that you can't keep
21:33 --> 21:35fooling the cancer for very long.
21:35 --> 21:37They the cancer figures out this
21:37 --> 21:39trip quite fast that you're trying
21:39 --> 21:42to inhibit it in this in this domain,
21:42 --> 21:44and they and the cancer makes changes
21:44 --> 21:46that diminish the drugs impact.
21:46 --> 21:48Whereas I think the antibody
21:48 --> 21:51approach is is is a more brute
21:51 --> 21:53force approach and it's harder for
21:53 --> 21:55the cancer to overcome this,
21:55 --> 21:57the strategy of inhibition.
21:57 --> 22:00I think the the therapeutic future
22:00 --> 22:02will likely use a combination
22:02 --> 22:04of these two to completely.
22:04 --> 22:08Dismantle the the out machinery.
22:08 --> 22:10In some ways you know cancer can be
22:10 --> 22:13feod viewed as having some of the
22:13 --> 22:15similar challenges that we see for SARS,
22:15 --> 22:18Co V2 and both use similar
22:18 --> 22:20strategies to overcome disease.
22:20 --> 22:23Both you know cancer and
22:23 --> 22:25viruses mutate rapidly.
22:25 --> 22:27And they can evolve to
22:27 --> 22:29different inhibitor approaches.
22:29 --> 22:32And just as we use antibodies
22:32 --> 22:35through vaccination or or directly
22:35 --> 22:37injecting recombinant antibodies and
22:37 --> 22:40small molecules to overcome COVID.
22:40 --> 22:44Now we have a new blueprint for ALK to
22:44 --> 22:46help us overcome similar challenges
22:46 --> 22:48that are encountered in in cancer
22:48 --> 22:50and in particular neuroblastoma.
22:51 --> 22:55And it sounds like when you know the the
22:55 --> 22:57structure of these aircraft carriers.
22:57 --> 23:00But you can be very specific about
23:00 --> 23:02you know targeting those particular
23:02 --> 23:05molecules as opposed to normal cells.
23:05 --> 23:08So you might have you know
23:08 --> 23:10a bomber that only targets,
23:10 --> 23:12you know that flatbed where the
23:12 --> 23:15aircraft lands on the aircraft carrier.
23:15 --> 23:18Or you can have some sort of a.
23:18 --> 23:21A mechanism whereby these two aircraft
23:21 --> 23:24carriers can't line up together that really
23:24 --> 23:27wouldn't apply in any other situation,
23:27 --> 23:29so you can try to get more precise
23:29 --> 23:31or more targeted therapies.
23:31 --> 23:32Is that right?
23:33 --> 23:34That's exactly right,
23:34 --> 23:37and remember that I said that you know,
23:37 --> 23:40since alpha is expressed only
23:40 --> 23:42on neuroblastoma cells but not
23:42 --> 23:44present on healthy tissue,
23:44 --> 23:45it really makes targeting
23:45 --> 23:47ALK the perfect for you know.
23:47 --> 23:49Set up for precision medicine
23:49 --> 23:51and then a layer on top of that,
23:51 --> 23:53which I think you were just referring
23:53 --> 23:57to is now that we know the detailed
23:57 --> 23:59structure and blueprints of this.
23:59 --> 24:00And that's exactly what we're trying to do.
24:00 --> 24:02We're trying to design
24:02 --> 24:03antibodies that specifically.
24:03 --> 24:07Block areas on the protein that are
24:07 --> 24:09involved in important for it's activation.
24:09 --> 24:12That is precisely where the ligand
24:12 --> 24:17binds to activate the receptor and
24:17 --> 24:19getting back to how it's activated.
24:19 --> 24:22Where we see the the two molecules
24:22 --> 24:24lining up side-by-side to each other,
24:25 --> 24:27we're designing antibodies that can
24:27 --> 24:29block that interface to prevent it
24:29 --> 24:31from being activated that is being
24:31 --> 24:33activated independent of ligand.
24:33 --> 24:36Which could be caused by certain mutations,
24:36 --> 24:38which is further research that we're
24:38 --> 24:41doing now or or with the ligand.
24:41 --> 24:45So we're using all this information
24:45 --> 24:47to specifically design antibodies
24:47 --> 24:50that are tailored to this molecule
24:50 --> 24:53and the and the type of mutations
24:53 --> 24:55or mechanisms that activate it
24:55 --> 24:58specifically in in neuroblastoma.
24:59 --> 25:02And so as you design these
25:02 --> 25:04antibodies in these treatments,
25:04 --> 25:06you're doing that in the lab. How?
25:06 --> 25:08How does it actually get into patients?
25:09 --> 25:11How does it affect people like your sister?
25:11 --> 25:14Because that's where the story
25:14 --> 25:16really started and how long
25:16 --> 25:18does that whole process take?
25:19 --> 25:21You're right, that's a that's certainly
25:21 --> 25:24is is a long process and you know
25:24 --> 25:26Cancer Research is is so matured and
25:26 --> 25:29specialized now that it really requires
25:29 --> 25:31you know effort to put these discoveries
25:31 --> 25:33into usable formats and for others
25:33 --> 25:36to build upon and meaningful ways.
25:36 --> 25:39And just as the NIH created that MSTP
25:39 --> 25:42program to link basic science and patient
25:42 --> 25:45Care now I think we need similar links
25:45 --> 25:47between basic science researchers.
25:47 --> 25:50I mean, the you know RNA biologist
25:50 --> 25:52and chromosome researcher and.
25:52 --> 25:54And in the biophysicist like me
25:54 --> 25:56trying to link up with the model
25:56 --> 25:59Organism biologist to test the a lot
25:59 --> 26:01of these and preclinical setups.
26:01 --> 26:04We all speak a different scientific dialect
26:04 --> 26:06and we have different perspectives,
26:06 --> 26:10so you know how do we work together
26:10 --> 26:12and in one answer to that is is,
26:12 --> 26:14you know being part of the Yale Cancer
26:14 --> 26:17Biol Biology Institute that I'm a part of.
26:17 --> 26:19You know we we really bring
26:19 --> 26:21together desperate researchers among
26:21 --> 26:23those interested in cancer.
26:23 --> 26:26And so you know now I have and and
26:26 --> 26:29being a physician scientist so you know
26:29 --> 26:32now there's a cohort of people and
26:32 --> 26:35colleagues that I can work with that
26:35 --> 26:37can bring our developing antibodies
26:37 --> 26:40that we have into preclinical testing
26:40 --> 26:43quite rapidly to see if they do.
26:43 --> 26:48So good activity in vivo and then that
26:48 --> 26:50hopefully can be rapidly leveraged
26:50 --> 26:53into reaching the the patients that
26:53 --> 26:55desperately need these treatments.
26:56 --> 26:58Sounds very much like you
26:58 --> 26:59had mentioned earlier,
26:59 --> 27:02but this is kind of a microcosm for
27:02 --> 27:04the macrocosm of how science works,
27:04 --> 27:06that that your lab puts together.
27:06 --> 27:09People who all kind of come at
27:09 --> 27:12the problem of of ALK from a
27:12 --> 27:13slightly different vantage point.
27:13 --> 27:17But the work in your lab kind of builds
27:17 --> 27:19on the work of other people's labs,
27:19 --> 27:22and so maybe in in the last
27:22 --> 27:24few minutes that we have,
27:24 --> 27:26you could tell us kind of a little bit about.
27:26 --> 27:29How that works in the grand scheme of things?
27:29 --> 27:31I mean, it sounds like.
27:31 --> 27:33One of the things that we've realized with
27:33 --> 27:35the pandemic is that the world is shrinking,
27:35 --> 27:38and hopefully the scientific discovery
27:38 --> 27:41from one lab to another kind of.
27:41 --> 27:43Bounces around fairly easily.
27:43 --> 27:45How does that collaboration work?
27:46 --> 27:49I think it is. It is certainly a challenge
27:49 --> 27:51and I think you know getting getting
27:51 --> 27:54researchers to to talk to each other and
27:54 --> 27:57work together is an important part of that.
27:57 --> 28:00And like you said, I think you know
28:00 --> 28:03during the pandemic and having people
28:03 --> 28:06communicate in different ways like we
28:06 --> 28:08are now through zoom and other things.
28:08 --> 28:11Maybe the world is shrinking a bit and I
28:11 --> 28:13think that's a good thing for science and
28:13 --> 28:16that's a good thing for research because.
28:16 --> 28:19Of course, all of us working
28:19 --> 28:21independently and making advances.
28:21 --> 28:23We don't want them to go unnoticed
28:23 --> 28:25by the people next in that chain
28:25 --> 28:26that you were talking about.
28:26 --> 28:28That's necessary to make the
28:28 --> 28:30leap to bring these discoveries
28:30 --> 28:32to their therapeutic potential.
28:33 --> 28:35Doctor Daryl Klein is an assistant
28:35 --> 28:37professor of pharmacology at
28:37 --> 28:38the Yale School of Medicine.
28:38 --> 28:40If you have questions,
28:40 --> 28:42the address is canceranswers@yale.edu
28:42 --> 28:44and past editions of the program
28:44 --> 28:47are available in audio and written.
28:47 --> 28:48Farm at yalecancercenter.org.
28:48 --> 28:51We hope you'll join us next week to
28:51 --> 28:53learn more about the fight against
28:53 --> 28:55cancer here on Connecticut Public
28:55 --> 28:56radio funding for Yale Cancer Answers
28:56 --> 29:00is provided by Smilow Cancer Hospital.

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March 27, 2022

Yale Cancer Center

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