Targeting Drug Tolerant Persister State in Lung Cancer

Transcript

• 00:00So I'm Roy Herbst,
• 00:01Deputy Director here at the Cancer Center,
• 00:04and it's really my honor to
• 00:06introduce the Cal Brazy Lecture.
• 00:09And this year you'll you'll
• 00:10meet Doctor Pasiani,
• 00:11who will be introduced by our lung program,
• 00:13scientific leader Katie Poletti and
• 00:15clinical leader Sarah Goldberg.
• 00:17But first, I just want to
• 00:18say a word about Paul
• 00:22Paul. Cal Brazy is often referred to as
• 00:24the father of oncology and its influence
• 00:26here at Yale Cancer Center remains a
• 00:28former faculty member at Yale School
• 00:30of Medicine who was internationally
• 00:32recognized as an authority on the
• 00:34pharmacology of anti cancer agents.
• 00:36Doctor Calabrazi serves as director
• 00:38of the Yale Cancer Center's Advisory
• 00:40Board until 2003 and we honor him
• 00:42with a conference room WW2 O 8
• 00:45where his picture hangs and I bet
• 00:47almost everyone here has visited.
• 00:49You can see here's the conference room
• 00:51shown on the slide with a beautiful
• 00:53portrait of Paul and all the lecturers,
• 00:55the 13 who have given this lecture over
• 00:58the last 14 or 15 years have shown and
• 01:00Doctor Yanni's plaque is already there
• 01:02and you can see the outside of the room.
• 01:04So if you haven't been to the room,
• 01:05go visit.
• 01:05We were just there and it was just
• 01:07wonderful to be with the Cal Brazy
• 01:09family and I welcome them all here
• 01:11today and to take some photos.
• 01:13This is a list of the lecturers.
• 01:15This is a very important lecture.
• 01:17You know, Paul was you know who
• 01:19who here has AK12 award?
• 01:21Do we have any of our K12 awardees here?
• 01:24They'll be.
• 01:25Yep, Yep so. So we have.
• 01:27So K12 is the Calabresi award.
• 01:30Paul was all about mentorship,
• 01:31teaching, taking care of the patient.
• 01:34He was both a scientist and a clinician.
• 01:37The the true what we used to
• 01:38call the three legged stool.
• 01:40So we try to invite people to these lectures
• 01:43and you can see the list of lecturers.
• 01:45And the very first one was Eddie Chu,
• 01:47also a mentee of Paul.
• 01:48And last year we had Steven Rosenberg.
• 01:53And here are just some photos over the years.
• 01:56It's very special lectureship for me
• 01:58because I actually met Paul 44 years ago.
• 02:01And how did I meet Paul?
• 02:03I have a picture,
• 02:04I can only find 2 pictures on the left,
• 02:07that's Paul behind his wife Seal.
• 02:08And that's me at my friend
• 02:10Peter Calabresi's wedding,
• 02:11the only picture Janice could find for me.
• 02:14But Paul was mentoring me and how
• 02:16to walk and stand stand up straight.
• 02:18And then on the right Paul took this picture.
• 02:21There's another picture with
• 02:22Paul but I couldn't find it.
• 02:23But that's Peter and I just a few
• 02:25years ago probably around 1983.
• 02:27You can see I'm I'm drinking a tab but,
• 02:30but, but but Paul was a mentor
• 02:32to me as to so many.
• 02:34That's always so special
• 02:35for me to have this lecture.
• 02:36And here we have Paul's
• 02:38brother Guido in the audience.
• 02:40His wife Ann was with us last night.
• 02:42His sons Peter and Steven.
• 02:45His daughter Janice Mimi,
• 02:47who is Steven's wife.
• 02:48So it's just wonderful to have
• 02:50the Calabrazi family here.
• 02:52But now to introduce our guest of the day,
• 02:54our speaker,
• 02:55I'm going to invite Sarah Goldberg and
• 02:56Katie Paletti to introduce Doctor Yanni.
• 03:00Good
• 03:06morning everyone.
• 03:07So this is really so such so wonderful
• 03:11to see everyone here and to meet and
• 03:13get to know the the Calabrazi family.
• 03:15But right now my my job is
• 03:17to introduce our speaker.
• 03:18So it is my absolute honor to
• 03:20introduce my colleague and friend,
• 03:22Doctor Pasiani as our guest lecturer for
• 03:24the Paul Calabresi Memorial Lecture Series.
• 03:27Doctor Yanni earned his MD as well as PhD
• 03:30degrees from the University of Pennsylvania.
• 03:32He then completed postgraduate training
• 03:34in internal medicine at Brigham and
• 03:37Women's Hospital and in Medical Oncology
• 03:39at Dana Farber Cancer Institute.
• 03:40He's currently the director of the
• 03:42Lowe Center for Thoracic Oncology and
• 03:44the scientific director of the Belfer
• 03:46Center for Applied Cancer Science.
• 03:48And he's also professor of Medicine
• 03:50at Harvard Medical School and
• 03:51the David M Livingston,
• 03:52MD Chair at Dana Farber.
• 03:55So it was at Dana Farber that I
• 03:56first met posse when I was a fellow.
• 03:58It was several years ago now as we
• 04:00were reminiscing about last night,
• 04:01I worked in his clinic and still now,
• 04:03you know as we both see patients
• 04:05with lung cancer,
• 04:06we we sometimes still share patients.
• 04:08And I can personally attest that he
• 04:10really is a fantastic oncologist who goes
• 04:13above and beyond for every single patient.
• 04:15So I'm going to now turn over to
• 04:17to Katie Politi to tell you a bit
• 04:19about Doctor Yanni's remarkable
• 04:20scientific contributions and PASI,
• 04:22I'm really looking forward to your lecture.
• 04:25Thank you, Sarah.
• 04:27Bon giorno E benvenuti attuti specialmente
• 04:30a la familia calabresi E aldotor pasi Yanni.
• 04:35As I said,
• 04:36good morning and welcome to everybody
• 04:39and especially to the Calabrese
• 04:42family and to Doctor Pasiyani Today.
• 04:45The advances in lung cancer treatment
• 04:47over the past 20 years have been
• 04:50remarkable and are contributing to
• 04:52a reduction in lung cancer deaths
• 04:54that we've seen in recent years.
• 04:57Doctor Yanni's research has played a
• 04:59central and critical role in contributing
• 05:02to the better outcomes for patients
• 05:04with lung cancer that we see today.
• 05:07His main research interests include
• 05:10studying the therapeutic relevance of
• 05:12oncogenic alterations in lung cancer.
• 05:14He was one of the Co discoverers of
• 05:17epidermal growth factor mutations
• 05:19in lung cancer and has pioneered
• 05:21the development of therapeutic
• 05:23strategies for patients with EGF
• 05:25receptor mutant lung cancer.
• 05:27His lab based and clinical research has
• 05:30also focused on other oncogenic driver
• 05:33subsets like those for those patients
• 05:36whose tumors harbor K Ras mutations.
• 05:38As you will see today,
• 05:40Doctor Yanni's laboratory research is
• 05:42at the forefront of addressing major
• 05:44challenges in lung cancer and sets
• 05:46the stage for advancing approaches for
• 05:49clinical treatment of the disease.
• 05:51Thank you Pasi for being here today.
• 05:53It's a pleasure to have you here
• 05:55for this lecture.
• 05:59We're going to take a picture
• 06:01with a both Reef before
• 06:02we start because and for inviting
• 06:04child raising family to come up.
• 06:06I'm also going to ask Lori Pickens,
• 06:07our Senior Vice President from Smile,
• 06:09to join us and we'll take the obligate
• 06:12picture that will be in direct
• 06:14connect and we're how do you want us?
• 06:29How was he going to do that?
• 06:30So why have to come? The
• 06:35screen, by
• 06:39the
• 06:42way, went to a shoe up.
• 06:50What invited speaker knows they
• 06:52only get 15 minutes to clock,
• 06:54but we will have.
• 06:54By the way, at the end,
• 06:55we're having mentorship testing.
• 06:56With any training you would like to
• 06:59say we're going to have all the images.
• 07:02Could we kill this just for a second?
• 07:04Just for a quick second? Sure. Thanks.
• 07:23Good luck at lunch.
• 07:29Thank you so much. Thank you. I'll
• 07:36put it over here.
• 07:46Thank you for those wonderful
• 07:49introductions and thank you Roy and
• 07:51entire team for inviting me here.
• 07:54And thank you for the Calabrese family.
• 07:56It was lovely to meet all of you yesterday
• 08:00at dinner and and and and today as well.
• 08:04So I will focus my lecture today on
• 08:11on a specific area of lung Cancer
• 08:15Research that we call drug tolerant
• 08:19persisters and you'll see what
• 08:21that all means in a few moments.
• 08:24These are my disclosures.
• 08:25I work with lots of companies
• 08:28to try to develop new therapies
• 08:30and hence the disclosures. So as
• 08:36Doctor Goldberg mentioned,
• 08:38lung cancer therapies have changed
• 08:42quite a bit and we think of lung cancer,
• 08:44especially lung adenocarcinoma,
• 08:45which is the most common form of
• 08:48lung cancer today as as a cancer that
• 08:52harbors potentially targetable genetic
• 08:55alterations shown in this pie chart.
• 08:59And if we actually look at what
• 09:03has been approved as therapies
• 09:06for these different alterations,
• 09:08we actually have a large number of
• 09:11therapies and more coming all the time
• 09:13approved for specific subsets of lung cancer.
• 09:16And so when we see patients in the clinic,
• 09:19one of our first questions is to try
• 09:21to understand does the cancer in that
• 09:23individual harbor one of these genetic
• 09:25alterations that we could then use one
• 09:26of the therapies on the right hand
• 09:29side or enroll that patient into a
• 09:31clinical trial that may be evaluating a
• 09:33new therapy or a therapeutic combination.
• 09:35And the therapies are successful.
• 09:39However, they still don't cure
• 09:43patients with advanced lung cancer.
• 09:46They're better than than what we
• 09:49would have had 2025 years ago,
• 09:52which is chemotherapy,
• 09:53but we still need to continue to do better.
• 09:57And So what typically happens,
• 09:58and this is an example of a patient
• 10:01with a lung cancer and he's treated
• 10:03with a targeted therapy and you can see
• 10:06almost all of the cancer disappears,
• 10:09but then it ultimately comes back.
• 10:12And what I'll focus my discussion today
• 10:14and what my lab has focused a lot is
• 10:17trying to understand why does it almost,
• 10:20almost completely disappears,
• 10:23but not completely disappear.
• 10:26And if we made this sort of
• 10:29intermediate state completely disappear,
• 10:32would our therapies be more effective?
• 10:36So let's look at it at a kind
• 10:39of A at this level.
• 10:41So,
• 10:42so example of a cancer we call this
• 10:44this sort of intermediate state the the
• 10:47persistor state or the drug tolerant
• 10:49persistor state out of which cancer
• 10:52various resistance mechanisms that we
• 10:54can detect clinically ultimately arise.
• 10:57Sometimes resistance mechanisms
• 10:59can pre-existing cancers and when
• 11:01you treat them with therapies they
• 11:04can out outgrow it and and and and
• 11:07develop resistance in that way.
• 11:08But this is definitely as as shown
• 11:11in those scans before happens as
• 11:13well and so how,
• 11:14how,
• 11:14how can we do better well we can
• 11:16develop therapies that are more
• 11:18effective at this initial therapy
• 11:20stage to eliminate this intermediate
• 11:23state or we can treat or figure out
• 11:26what make what's unique about this
• 11:29intermediate state and how could
• 11:31we eliminate it and ultimately
• 11:34delay or prevent resistance.
• 11:37So one and and and as as as as you
• 11:42heard from the introduction, I,
• 11:43I focus on EGFR mutant lung cancer,
• 11:45which in that pie chart is not
• 11:48quite the biggest,
• 11:49sort of the second biggest piece of the pie.
• 11:51And we were involved in that initial
• 11:54discovery and have subsequently tried
• 11:56to develop therapies for patients who
• 11:59are treated with EGFR inhibitors.
• 12:01And one of the things that we're
• 12:04recently involved in was asking
• 12:06can we use another therapy such
• 12:09as chemotherapy that we
• 12:12commonly use in lung cancer in
• 12:13combination with an EGFR inhibitor.
• 12:15And would that in fact lead to
• 12:18a better outcome for patients
• 12:20compared to an EGFR inhibitor alone.
• 12:24And that could be because it's
• 12:26more effective initially or it
• 12:28impacts this intermediate state.
• 12:32And so this is a clinical trial that
• 12:34those of you who treat lung cancer
• 12:36patients are probably familiar with
• 12:37called the FLORA two trial where
• 12:40the standard of care EGF inhibitor
• 12:42ASA mertnib also known as Tagrisso
• 12:45was combined with chemotherapy
• 12:47compared to the ASA mertnib alone.
• 12:49And patients got combination chemotherapy
• 12:52and then followed by maintenance
• 12:55chemotherapy and and ASA mertnib.
• 12:58And this trial turned out to
• 13:00be a positive in in terms of
• 13:03progression free survival sort of
• 13:05delaying the likelihood of
• 13:10recurrence from or disease growth from
• 13:15lung cancer significantly depending
• 13:17on how how it was looked at by the
• 13:20investigators or by blinded review.
• 13:23It delays that by about nine months which
• 13:27which has clinical implications as well.
• 13:31It was especially effective in patients
• 13:33who whose cancer had metastasized
• 13:36to the brain this this difference
• 13:38is larger but even in patients
• 13:40who where that wasn't the case,
• 13:42it was effective.
• 13:43And if we look at the common
• 13:45types of EGFR mutations about the
• 13:47of the common ones about 50% are
• 13:49these Exxon 19 deletions and 50%
• 13:51are these Li 58 arm mutations.
• 13:53And in both cases chemotherapy improved
• 13:56the outcome of of of of the patients.
• 14:02It's it's too early to know whether
• 14:06this improvement translates
• 14:08into patients living longer.
• 14:10We'll hopefully have some updates
• 14:12later on this year on on that.
• 14:14But it did delay the what we call
• 14:17the 2nd progression free survival.
• 14:19So the time
• 14:23of so patients who got chemotherapy
• 14:25and an EGFR inhibitor first even if
• 14:28they got subsequent therapy it's
• 14:31still that was still effective.
• 14:34They they had a longer durability
• 14:37of benefit than if they just
• 14:40started the EGFR inhibitor.
• 14:42Now if we look at kind of trying
• 14:44to understand what is what is
• 14:47chemotherapy doing now it turns out
• 14:49that the this is the EGFR inhibitor
• 14:51alone and this is chemotherapy,
• 14:53these look very similar.
• 14:54This is, these are all individual
• 14:56patients and the degree or or so
• 14:59this is what we call a waterfall
• 15:01plot and these are all patients were
• 15:03measuring their tumor shrinkage.
• 15:05And what was maybe disappointing
• 15:09is that even with the addition of
• 15:12chemotherapy the the maximum or
• 15:16median best tumor shrinkage was
• 15:1950% in the EGFR inhibitor and only
• 15:2352.6% when you added chemotherapy.
• 15:26However,
• 15:27the durability of that shrinkage
• 15:29was much longer,
• 15:31about nine months longer if you
• 15:33had chemotherapy compared to the
• 15:35EGFR inhibited by itself.
• 15:37But it still means that there are
• 15:39cancer cells that are able to
• 15:42survive despite EGFR inhibition and
• 15:44and and and this is an area that we
• 15:48have focused pre clinically quite
• 15:49a bit and asked the question what
• 15:52sort of dictates the dichotomy of
• 15:54a of a of a of a cancer cell from
• 15:57dying versus surviving these cancers
• 16:00that have these EGFR mutations.
• 16:01This represents a cancer and
• 16:03these are individual cells.
• 16:04All of the individual cells
• 16:05have the EGFR mutation.
• 16:07So it's not like the ones that survive
• 16:09don't have the EGFR alteration,
• 16:10they do but they figure out ways
• 16:13to survive whereas others die.
• 16:14And several years ago we we
• 16:19recognize that one of the downstream
• 16:22pathways from EGFR map,
• 16:23kinase pathway are here as measured
• 16:26here by phosphorylation of URC is
• 16:29turned here it's on here it's off but
• 16:32within a few days it comes back on
• 16:34and if you block this pathway with
• 16:37a a MEC inhibitor here trimetinib,
• 16:39you can prevent that from happening.
• 16:42So why is that important?
• 16:43Well,
• 16:44the way EGFR inhibitors cause cancer
• 16:47cells to die is they down regulate
• 16:50this pathway as I've shown here that
• 16:53bath that leads to up regulation
• 16:56of a proipoptotic protein called
• 16:58BIM and then leads to cell death.
• 17:00And so now EGFR inhibition is decoupled
• 17:03from down regulating of this pathway.
• 17:05Now you've provided a a way
• 17:07for the cells to survive,
• 17:09turn this pathway on and and survive.
• 17:14And so here we can block it with a
• 17:17drug trimetinib, our MEC inhibitor.
• 17:19And we're trying to evaluate this in
• 17:22the clinic by doing a clinical trial
• 17:24combining an EGFR inhibitor here
• 17:26with a MEC inhibitor called solumettinib.
• 17:29And here we have to give it
• 17:32intermittently 4 days on,
• 17:34three days off because when these
• 17:35drugs are given by themselves,
• 17:37they have side effects,
• 17:39typically skin side effects and
• 17:40fevers and other side effects.
• 17:42And so we can't give both the EGFR
• 17:45inhibitor and the MEC inhibitor every day.
• 17:48Now whether this intermittent
• 17:50schedule achieves the same biologic
• 17:52outcome that we saw in the laboratory
• 17:56setting remains to be seen.
• 17:59Now despite doing those two therapies,
• 18:03if we look at cells under the microscope,
• 18:07they're still surviving cells
• 18:11even when we add those
• 18:13two combinations together.
• 18:14And if we analyze the cells that
• 18:16after one day of giving the drugs
• 18:17or 21 days after giving the drugs,
• 18:19we can see that all of the sort
• 18:21of EGFR and pathways are turned
• 18:23off including ERC because we're
• 18:25using that the MEC inhibitor here.
• 18:27If you withdraw those,
• 18:29if you then wash out the drugs,
• 18:31the cancer actually regrow regrows
• 18:33that we call rebound cells and all
• 18:36of those pathways are once again on.
• 18:39And so we had wondered how is
• 18:44it that they survive and they
• 18:47survive through up regulating
• 18:49another signaling pathway called
• 18:51the Hippo signaling pathway,
• 18:53namely a protein called Yap that
• 18:58normally when it's turned on or
• 19:02up regulated which happens in
• 19:03response to EGFR and MEC inhibition,
• 19:06it turns off the expression of A
• 19:10pro apoptotic sensitizer called BMF.
• 19:13And so if you now block this
• 19:15in any way genetically deleted
• 19:17or use drugs against this,
• 19:20you now up regulate this protein.
• 19:22It can release more of the apoptotic
• 19:26proteins namely BIM from anti
• 19:28apoptotic proteins and it can
• 19:31shift cell survival to cell death.
• 19:33And so that's another.
• 19:35So it's basically another counter
• 19:37regulatory mechanism by which
• 19:38cancer is used to survive.
• 19:40And this is just to prove that you
• 19:43actually need if you if you use
• 19:45genetic tools to knock out this BMF,
• 19:47you don't see the the the increased
• 19:50cell death here compared to if
• 19:52it's if it's not knocked out.
• 19:54And the good thing is there are now
• 19:56companies that make TEED inhibitors.
• 19:59This Yap protein interacts with
• 20:02another protein called TEED and
• 20:03there are multiple companies that
• 20:05are making these inhibitors and
• 20:07if we use these inhibitors.
• 20:08Here if we measure cell death in red,
• 20:10when we add one of these inhibitors,
• 20:12they increase cell death from
• 20:13blue to red and we hope that this
• 20:16is clinically meaningful.
• 20:17They're being mostly tested in
• 20:20initially in malignant mesothelioma,
• 20:22but they there are hopes that
• 20:25these will move towards testing
• 20:28in in lung cancers as well.
• 20:30So I mentioned the two kind
• 20:33of regulatory pathways.
• 20:34We then wanted to ask another
• 20:36question by studying this state and
• 20:38ask is there something that we can
• 20:40you know if we these are to enhance
• 20:42the initial effect of the therapies.
• 20:44I'll shift to talking about this
• 20:47cell state and ask are these are
• 20:50the unique vulnerabilities within
• 20:51this actual cell state.
• 20:53And when we did this prior study
• 20:55where we
• 21:00found this Yap teed pathway,
• 21:02we recognize that the cells that
• 21:05survive in after a inhibition with
• 21:07an EGFR inhibitor or any other
• 21:09inhibitor in the right genetic context,
• 21:12they have features of cellular senescence,
• 21:16so aging cells and it it doesn't
• 21:19matter how you characterize them,
• 21:21they all have this is a,
• 21:23they're often they stain blue and
• 21:25this beta galactosidase stain
• 21:26and they have other features that
• 21:28are all found in these cells.
• 21:30Now it's not true cellular senescence
• 21:32because true senescence is irreversible
• 21:35unfortunately as all of us are aging.
• 21:38But this is a reversible state
• 21:40because as I mentioned earlier
• 21:41if you take the drugs off,
• 21:42the cancer cells will start to to grow.
• 21:45And and there is a whole field
• 21:48of developing drugs trying to
• 21:51treat senescent cells and they're
• 21:54often referred to as Senalytics.
• 21:57And what we so we wanted to do is
• 22:01first treat our cancer cells with
• 22:04an EGFR inhibitor and then treat him
• 22:07with another drug to ask can we in
• 22:10this red example can we find drugs
• 22:13that would specifically eliminate
• 22:15or be toxic to those cells that are
• 22:18in this state And and when we look
• 22:20through and and screened all of them,
• 22:23the ones that
• 22:26scored in the top are inhibitors of BCLXL
• 22:32which is an anti apoptotic protein.
• 22:37So by inhibiting that you can again
• 22:40shift cells more to dying as opposed
• 22:43to surviving and this is enriched
• 22:46in the in the senescent state.
• 22:51So if that's true
• 22:52then we should be able to show that
• 22:54experimentally and so we first did this
• 22:56experiment where we took mice that have a
• 23:00carry a xenograft of an EGFR mutant cells.
• 23:02We treated them with a control or
• 23:05with the EGFR and MEC inhibitor
• 23:07combination for three weeks and after
• 23:09three weeks we split half the mice
• 23:11to continue the EGFR MEC inhibitor or
• 23:14added a BCLXL inhibitor Nabita Clex.
• 23:16And then we treated for another three weeks
• 23:20and then we stopped all the drug treatments.
• 23:22And we asked is there is there a
• 23:26difference in growth regrowth of the of
• 23:28the cancer in the in the model that just
• 23:31got the EGFR MEC inhibitor compared to
• 23:33the one that got the BCLXL inhibitor.
• 23:36Because if we if if if our hypothesis
• 23:39is correct at this state that persistent
• 23:42state has been established and if
• 23:43they're sensitive to the nevita clax,
• 23:45we should eliminate more of the
• 23:47cells and then it should delay the
• 23:50regrowth of the tumor.
• 23:52And it does a little bit in green
• 23:54here although you could argue that
• 23:56this is probably pretty marginal.
• 23:58This is so the treatment,
• 23:59this is the day day 42 when we withdraw
• 24:02the the drugs and then compare growth.
• 24:05And here if you look at the
• 24:07individual animals,
• 24:08here's the the three drug combination,
• 24:10you can see that most of them still
• 24:12grow back although there are some
• 24:15that are completely eliminated.
• 24:17So we were wondering why may that be
• 24:20the the case and one possibility is,
• 24:23are we delivering the drugs to
• 24:26the to these persistent cells in
• 24:28in an efficient manner.
• 24:30And to get at that problem,
• 24:33we've worked with AbbVie,
• 24:35A pharmaceutical company that has
• 24:38developed an antibody against EGFR
• 24:40that's coupled to a BCLXL inhibitor.
• 24:44So this is a more of a targeted
• 24:46called an antibody drug conjugate.
• 24:48So it's a more targeted way of
• 24:51delivering the BCLXL inhibitor
• 24:52specifically to cells that express
• 24:55EGFR like the cancer cells that we're
• 24:58interested in And it and that has
• 25:00the advantage of avoiding potential
• 25:02systemic toxicities because if you
• 25:04just give the inhibitor by itself,
• 25:05one of the toxicities that's been
• 25:07seen in the clinic is thrombocytopenia
• 25:09or lowering of platelet counts
• 25:11because this protein is important
• 25:13for maturation of the platelets.
• 25:14And so if you give the drugs will there
• 25:17go to the tumor and to the bone marrow,
• 25:19you'll start to see patients
• 25:21platelet counts decrease.
• 25:24And this is just to show that in from ADVI,
• 25:27if they use a small molecule inhibitor,
• 25:31here's normal platelets, they go down.
• 25:33But if he uses antibody drug conjugate
• 25:35since the this is not cleaved normally
• 25:38except when it's internalized into the cell,
• 25:40you don't see that much
• 25:42of A platelet reduction.
• 25:46So and in ABB Vie's experiments
• 25:48when they've done given the EGFR
• 25:51inhibitor together with this antibody
• 25:53drug conjugate from the beginning,
• 25:56they can certainly delay the
• 25:58regrowth of cancer cancers in
• 26:00in these two different models.
• 26:02But that wasn't exactly the
• 26:03question that we were after.
• 26:04We were after this question,
• 26:05what happens in that persistent state.
• 26:07So we kind of redid that experiment here
• 26:09using the EGFR inhibitor alone where
• 26:12we then after 21 days half the mice
• 26:15will continue the EGFR inhibitor alone,
• 26:17half the mice will continue the
• 26:19EGFR inhibitor and get this e.g.
• 26:22FRBCLXL antibody drug conjugate for
• 26:24another three weeks and then we
• 26:26withdraw the drugs and follow outgrowth
• 26:29and here we see a much more dramatic
• 26:32difference and green is the the,
• 26:34the, the the double combination.
• 26:36You can see that here individual animals.
• 26:38So it's much more impressive than than
• 26:41the than using the nevitoclax alone and
• 26:44the and the animals tolerate it quite well.
• 26:48There are some some over
• 26:50long periods of time.
• 26:52This is like you know six months later
• 26:55we can look at the we can look at the,
• 26:58the,
• 26:58the,
• 26:58the animals and not all of them are cured.
• 27:01Some of them do regrow and we
• 27:03can detect the regrowth by using
• 27:05antibodies that specifically detect
• 27:06the mutiny GFR protein.
• 27:10Sometimes we see immune infiltrates
• 27:14and if he if you if we compare.
• 27:16So we can cure some of the animals
• 27:18with the EGFR inhibitor alone,
• 27:20but we can cure many more
• 27:21when we add this other agent.
• 27:24In the middle of treatment is
• 27:28another model that kind of
• 27:30shows the same same phenomenon.
• 27:32Unfortunately,
• 27:32they also do start to regrow
• 27:36after a period of time and so.
• 27:41So we see that some mice are cured,
• 27:42others are not and that could be for
• 27:45lots of reasons, it's a duration of
• 27:47treatment important in the clinic.
• 27:48We would typically continue a second
• 27:50therapy for much longer periods of time
• 27:52than we did in the animal experiment.
• 27:54And of course there are other proteins,
• 27:57other antipoptotic proteins that
• 28:00can sort of compensate for BCLXL
• 28:02inhibition such as MCL one.
• 28:03And that may be the reason that
• 28:06we're seeing some of those relapses.
• 28:08But ultimately we want to ask is this,
• 28:10is this something that can
• 28:12be applied in the clinic?
• 28:15And this is, this is a drug that
• 28:16is being tested in the clinic.
• 28:18It's called a BVAB BV637 made by Avi.
• 28:23And at this year,
• 28:25this past year's ESMO meeting,
• 28:26my colleague Julia Rotor from Dana
• 28:30Farber presented the clinical data
• 28:32of giving this agent by itself or
• 28:35in combination with chemotherapy
• 28:37or with with awesome mertinib.
• 28:39So here it's given monthly and the
• 28:42awesome mertinib is given every day.
• 28:44And the good thing is that the combination
• 28:46is actually quite well tolerated.
• 28:49There's some liver function
• 28:51abnormalities that you can see.
• 28:53But no, there was no major interactions,
• 28:55there's no major platelet decreases
• 28:57as we'd expect from the preclinical
• 29:00data and no bad toxicities that would
• 29:05get us worried about potentially
• 29:07moving this combination forward.
• 29:08So our our plan is to try to move
• 29:11that forward and use it in that same
• 29:13scenario and patients that we saw in the
• 29:17in the mouse models.
• 29:19And in fact in that presentation,
• 29:21these were all patients that have been
• 29:24treated previously with Asamertinib
• 29:25and in some of those patients that
• 29:27combination actually led to tumor
• 29:29shrinkage which was very nice to see
• 29:32and encouraging to helps move that
• 29:36forward for clinical development.
• 29:41So another, so I talked about that
• 29:43vulnerability and then the other option,
• 29:46other thing that we're doing is asking
• 29:48of this sort of intermediate state,
• 29:50are there novel targets that could be
• 29:53expressed in this state that we could
• 29:56go after with therapies that are in
• 29:59the clinic or therapies that need to
• 30:01be developed for clinical application.
• 30:04And so we've done some RNA sequencing
• 30:07analysis and untreated cells and cells
• 30:09that are in this sort of persist or
• 30:11state focusing on specifically looking
• 30:14at cell surface proteins as targets.
• 30:16And for many cell surface proteins
• 30:18there are antibody drug conjugates
• 30:20which are that are in the clinic.
• 30:22So antibodies linked to not in the, not,
• 30:25not the BCL XL inhibitor that I showed,
• 30:28but to chemotherapy and so having
• 30:30a more sort of targeted way of
• 30:33delivering chemotherapy to two cells.
• 30:35And these are just three of them.
• 30:37And we see them that they're both sort
• 30:40of enriched in that sort of state after
• 30:43treatment with an EGFR inhibitor here
• 30:46you can see them by by Western blotting.
• 30:49You can see in these EGFR mutant
• 30:52cancers this black band is this
• 30:54TROP 2 protein that's enriched after
• 30:56treatment with an EGFR inhibitor.
• 30:58This is full R1 which is a folate
• 31:01receptor that's also increased and
• 31:03it's not just limited to EGFR.
• 31:04Here are cells with other genetic
• 31:06alterations and ALK rearranged cell lines.
• 31:08We're treated with an ALK inhibitor.
• 31:09You can see the same thing,
• 31:11a Med amplified cell line treated with
• 31:13a Med inhibitor or K Ras mutant cell
• 31:15line treated with AK Ras inhibitor.
• 31:17You can see the the same things
• 31:21and
• 31:24again ALK and raw cell lines
• 31:26showing the showing the same thing.
• 31:28This is for the folate receptor and
• 31:30this is for trope trope too and we've
• 31:34also used our animal models and and
• 31:36and and some are cell line models,
• 31:38some are patient derived models to
• 31:41study that state that we I mentioned
• 31:43earlier in the presentation where
• 31:45we initially studied it from cells
• 31:48and grown in plastic but here we
• 31:50can study it from animals and here
• 31:52you can you can see the animals
• 31:53are treated with EGFR inhibitor,
• 31:55EGFR MEC inhibitor and they
• 31:57have these very nice responses.
• 31:59So the time of this maximum response
• 32:01we dissect out the kind of the
• 32:04residual area where the tumor is.
• 32:06We purify the tumor cells and
• 32:07can do all all different types of
• 32:09analysis on the tumor cells to ask.
• 32:11This has also happened in in in vivo as
• 32:14opposed to just in a tissue culture model.
• 32:17And so here's one example of different
• 32:21models treated with Asamertinib,
• 32:23Rasamertinib in the MEC inhibitor.
• 32:24This is the what the tumors look like
• 32:26when we dissect them out in the in
• 32:28the sort of minimal residual state.
• 32:30And if we look for expression of trope 2,
• 32:34we can see that it's a membrane
• 32:36bound protein.
• 32:36So you can see it expressed here
• 32:39more intensely than you see it
• 32:41in the in the untreated models,
• 32:43although you do see some expression
• 32:45in the untreated models.
• 32:46And if we quantify this,
• 32:48the models tend to have some baseline
• 32:51expression which is then enhanced with e.g.
• 32:54FREGFR MEC treatment and it kind of
• 32:56varies a little bit from model to model.
• 32:59This is the same experiment
• 33:00for this folate receptor.
• 33:01It seems to be much you don't
• 33:03find it in the untreated but you
• 33:06do find it in the treated one.
• 33:08So we like these kinds of examples
• 33:11because the hope would be that this
• 33:14is something that's specifically
• 33:16induced in the tumor cells and
• 33:18hence any therapeutic strategy
• 33:21should be should hopefully
• 33:22have a wider therapeutic index that it's
• 33:25targeting the tumor and not normal tissues.
• 33:27But wait to see that and here it's
• 33:31we look at it by RNA sequencing,
• 33:33same idea, we can look for these
• 33:36different cell surface proteins
• 33:38that are up regulated and for which
• 33:41there are antibody drug conjugates.
• 33:44And we also have a trial where
• 33:46we're trying to understand this.
• 33:47This actually happened in
• 33:49patients and so this is a trial,
• 33:51a very straightforward trial where
• 33:52newly diagnosed lung cancer patients
• 33:54were treated with Osamerton,
• 33:56they've been the EGFR inhibitor in the
• 33:58primary goal of the trial was to study
• 34:01how do cancers develop resistance to
• 34:03Asamerton when it's clinically visible.
• 34:06But what we built into this trial is
• 34:08that during the sort of maximal time that
• 34:10the person has had a response to therapy,
• 34:12we biopsy that area if we can find
• 34:15it and do analysis to see can we
• 34:19find these proteins expressed that
• 34:21I showed in the preclinical models.
• 34:23This is just an example of a patient.
• 34:25Here's two months of ASA Merton if not
• 34:27the most dramatic reduction but and
• 34:29here you may able to see the biopsy needle,
• 34:32we're biopsy in the individual and a
• 34:35study only has on treatment biopsy.
• 34:38So we don't have the pre treatment
• 34:40to compare it to.
• 34:41But at least by single cell RNA sequencing
• 34:43in the on treatment biopsies we can
• 34:45find a cluster of tumor cells that
• 34:47express trope here in this case trope 2.
• 34:49So at least we think that this is has
• 34:52some real relevance in patience and
• 34:57are trying to validate it further.
• 35:01So what is Trope 2?
• 35:03Trope 2's may be familiar for
• 35:06our clinical audience,
• 35:08but it's a intracellular calcium
• 35:10signal transducer that's over
• 35:13expressed in many epithelial cancers.
• 35:16There are agents that target trope 2.
• 35:18Here's an antibody linked to A
• 35:22chemotherapeutic agent in red here
• 35:24that's still infused intravenously
• 35:27and then binds the tumor cells and
• 35:29then this chemotherapeutic agent
• 35:31is internalized and cleaved in the
• 35:33tumor cells like a Trojan horse.
• 35:35And then specifically can can
• 35:39kill the tumor cells.
• 35:41And if we use this agent
• 35:42in lung cancer patients,
• 35:44you can see about 1/4 of patients
• 35:46have tumor shrinkage and some of them
• 35:48have more dramatic tumor shrinkage.
• 35:50This is given to a wide variety
• 35:52of patients with lung cancer.
• 35:54What we've learned over the last
• 35:56couple years is that it works
• 35:58perhaps particularly well in cancers
• 36:00that have the EGFR mutation.
• 36:03If we isolate this experiment to patients
• 36:05whose cancers have genetic alterations,
• 36:08about a third of them
• 36:09have real tumor shrinkage.
• 36:11And if you look at the specifics of them,
• 36:13most of these have EGFR mutant cancers
• 36:15although there are others in there as well.
• 36:17And but this year's ESMO meeting
• 36:18or last year's ESMO meeting,
• 36:20this was studied in more detail.
• 36:22And patients that have an EGFR mutation,
• 36:24they tend to have a greater response
• 36:27than cancers that have other
• 36:29genetic alterations for reasons
• 36:30that nobody understands yet.
• 36:32But it's something that we're
• 36:35keenly interested in investigating.
• 36:37So we then use that the same sort of
• 36:39in vivo model and ask the experiment
• 36:41if we now target this stroke two
• 36:44protein after this persistent state
• 36:46has been established, doesn't matter.
• 36:48So again treat the mice with asamertinib,
• 36:50some are, some continue on asamertinib
• 36:54and some are given this troph
• 36:572 antibody drug conjugate which
• 36:59is approved in breast cancer,
• 37:00not lung cancer.
• 37:01And in fact the clinical trial and
• 37:04lung cancer just failed unfortunately
• 37:06and again treat him and then we
• 37:10withdraw the drugs and there is
• 37:12a little bit of a difference.
• 37:13It's not humongous,
• 37:14but there's a little bit of a difference
• 37:16in the tumors that got treated with
• 37:19a Trop 2 antibody drug conjugate.
• 37:21On the other hand,
• 37:23when we take this out longer days,
• 37:26they all start to regrow.
• 37:27So we didn't really cure any of
• 37:30the mice here using this approach.
• 37:35So this Trop 2 protein expression
• 37:38increases following therapies that
• 37:40directed directed at the right
• 37:42genetic alteration in lung cancers.
• 37:45Adding this antibody drug conjugate
• 37:47once this tolerant state has been
• 37:50formed didn't really eradicate these
• 37:52cells because otherwise the cancers
• 37:54wouldn't have been able to grow back.
• 37:56And so where do we go from here?
• 38:00There are other antibody drug
• 38:02conjugates targeting this
• 38:03protein that may be more potent,
• 38:05which could be an issue here,
• 38:06one made by Dai Ichi and being developed
• 38:10by Dai Chi and AstraZeneca called DS1062A.
• 38:15Do we need to increase the
• 38:16duration of the treatment?
• 38:18Is that an issue here or can we
• 38:21develop some novel strategies here
• 38:22And and I'll I'll show you one
• 38:24novel strategy that we're evaluating
• 38:26that that and that is developing
• 38:29CAR T cells directed at trope 2.
• 38:33So chimeric antigen receptor T cell
• 38:37therapy type of immune therapy is being
• 38:41used in lots of hematologic malignancies
• 38:44and has done wonders there on a therapy.
• 38:49Just this strategy in general
• 38:52has struggled in solid tumors and
• 38:54part of the issue is that you're
• 38:57targeting you have to target a
• 38:59a specific cell surface protein.
• 39:02If that cell surface protein is
• 39:04also present in normal tissues,
• 39:05then you're then you're delivering this
• 39:08effective therapy to normal tissues
• 39:10and that can lead to a lot of toxicities.
• 39:12And so you need to try to
• 39:16identify two unique proteins,
• 39:18tumor antigens,
• 39:18proteins present on the surface of
• 39:20tumor cells that are not found on
• 39:22normal cells and that's remained a
• 39:24challenge in the solid tumor field.
• 39:26And this is work we've done with Eric
• 39:28Smith and Elliot Brea at Dana Farber.
• 39:32So this just shows you what
• 39:34these things look like.
• 39:36And so if we use these cells in again
• 39:39in a tissue culture model and we
• 39:42take those EGFR immune cancer cells
• 39:44and genetically remove trope 2.
• 39:47So the target of where the antibody is
• 39:49supposed to bind the the cells do nothing.
• 39:51Here in red and in green is a non
• 39:54specific or a a CAR T cell against the B
• 39:57cell antigen that isn't expressed at all.
• 40:00So if you knock it out or make a CAR
• 40:02T cell against an irrelevant protein,
• 40:04nothing happens.
• 40:05If you enter these knockout cells,
• 40:09replace the normal form of trope too,
• 40:12and now you can see less cells survive,
• 40:16or in the endogenous cells,
• 40:17less cell survives versus targeting
• 40:20AB cell antigen doesn't do anything.
• 40:23We of course wanted to make sure that
• 40:26the EGFR inhibitors weren't toxic
• 40:27to these CAR T cells and they're
• 40:30not except when you get to very
• 40:32high concentrations.
• 40:33So then we then we asked the experiment
• 40:35of first treating them with the EGFR
• 40:38inhibitor and tissue culture model and
• 40:40then to set up that drug tolerance state
• 40:43and then expose them to the CAR T cells.
• 40:46And.
• 40:47And similarly,
• 40:47if you've knocked out trope 2,
• 40:49nothing happens.
• 40:50And in the endogenous EGFR immune cells,
• 40:53they're very effective,
• 40:55Very few cells survive.
• 40:57And if you've replaced the
• 40:59normal into this knockout cell,
• 41:00replace the normal form of trope 2.
• 41:02So now it's expressed.
• 41:03Now they're once again effective
• 41:05like in the normal situation.
• 41:06So we do think it's doing what what we
• 41:10expected to be doing at least in in vitro.
• 41:13And we've now also again finally
• 41:15taken the same experiment and
• 41:17are starting to do it in vivo.
• 41:20Treat the tumors for 10 days or 21 days.
• 41:24Randomize them to continue EGFR inhibition.
• 41:28Use the continue with EGFR inhibition
• 41:30and the and the trope to antibody drug
• 41:34conjugate or a CAR T cell against
• 41:37the B cell antigen or against trope
• 41:40to just delivered once and then
• 41:43ask what happens to these animals.
• 41:47So they're delivered here.
• 41:48This is the schedule for the ADC
• 41:52delivery and then the CAR T cells
• 41:54are delivered also here at day 21.
• 41:57And you can see that the ones that
• 41:59are treated with the EGFR inhibitor
• 42:02alone all managed to regrow.
• 42:04The ones that are treated with the
• 42:07targeting an irrelevant protein
• 42:09also regrow and purple behind it.
• 42:12And the ones that are treated with the
• 42:14CAR T cell or in this case the ADC,
• 42:16the Sazotuzumabe and Goba T can't
• 42:19have the separation.
• 42:20And if we look at this long term,
• 42:22we certainly see that the ones
• 42:24that receive the trope 2 CAR T
• 42:25cell have a much better outcome.
• 42:27There are some escapers here
• 42:28and we're trying to understand
• 42:30why do they escape therapy.
• 42:31All of the ones treated with the ADC like
• 42:33in our prior experiments start to regrow.
• 42:35Similarly with the EGFR inhibitor by itself
• 42:37and and also most of the ones that are,
• 42:40there's one here most of the ones
• 42:42that are treated with irrelevant
• 42:44or B cell antigen CAR,
• 42:45T cell also start to regrow
• 42:47as as we'd expect.
• 42:51So I talked about this drug tolerant
• 42:55persistent state that can give rise
• 42:57to a broad range of actual drug
• 42:59resistance mechanisms and it's
• 43:01really one step why are one reason,
• 43:04not the only reason but one reason
• 43:07why are effective targeted therapies,
• 43:10precision therapies in lung cancer although
• 43:13effective they're not effective forever,
• 43:16they ultimately resistance happens
• 43:18in most if not all patients.
• 43:22And this state,
• 43:23what I'm trying to was trying to
• 43:25convince you is this state has some
• 43:27unique biologic properties and expressed
• 43:28potentially novel cell surface targets
• 43:30which can be leveraged therapeutically.
• 43:34And if we prevent the formation of this
• 43:37state or specifically treat the state,
• 43:39we may be able to extend the benefits of
• 43:43of our genotype directed therapies and
• 43:44lung cancers and maybe in other cancers.
• 43:47But this needs clinical validation and
• 43:50of course the issue that I mentioned
• 43:53that some of these proteins that are
• 43:54expressed in these drug tolerant states
• 43:56also expressed in normal tissues which
• 43:58may limit the therapeutic window and
• 44:01and again one reason why or 111 big
• 44:05reason why clinical validation is needed.
• 44:08So I just wanted to thank just acknowledge
• 44:10the many members of my laboratory who've
• 44:12been worked on these various projects.
• 44:14Here on the left hand side in the
• 44:17middle are my long term collaborators
• 44:19in the in this field,
• 44:20Nathaniel Gray who's a medicinal chemist,
• 44:22Mike Eck who is a structural biologist,
• 44:25biochemist and Kwak Wong who does
• 44:27animal models of lung cancer.
• 44:29We've worked,
• 44:30had the pleasure to work together
• 44:33for the last 10 years or so except
• 44:35during that time both Nathaniel
• 44:37and Kwak left Dana Farber.
• 44:38But we still continue to work together
• 44:41and still just submitted APO one together.
• 44:43So we'll hopefully be able to do this.
• 44:46The clinical,
• 44:47we have a lot of wonderful clinicians
• 44:50and clinical trialists who will run the
• 44:53clinical trials that I mentioned to you.
• 44:56That couldn't be done without our
• 44:58clinical research staff and patients
• 45:00and families who participate in clinical
• 45:03trials or translational research
• 45:05undergoing on treatment biopsies which
• 45:08may not benefit them directly but may
• 45:11ultimately help develop new therapies.
• 45:13We use a lot of bioinformatics in our
• 45:16analysis and with that couldn't be
• 45:19done without the bioinformaticians,
• 45:21the Belfer Centre that I helped run.
• 45:23These are many of the members are
• 45:24there and of course we need to have
• 45:27collaborators in the pharma industry
• 45:29who are developing many of these
• 45:30drugs to be able to
• 45:34to carry them out and hear some
• 45:36collaborators from AstraZeneca,
• 45:37Daiichi Sanchio and AbbVie.
• 45:40My collaborator Dave Barbie on
• 45:43the and Eric Smith and Elliot
• 45:46Abrea works with Eric and Dave
• 45:49on the on the car T cell studies.
• 45:52I just want to acknowledge them.
• 45:53And of course, none of the work
• 45:56would be possible without funding.
• 45:58And these are many of the
• 46:00funding agencies that have
• 46:04supported the work over the years.
• 46:06So I will stop there and happy to
• 46:08take any questions. Thank you again
• 46:10for the invitation to be here.
• 46:22Thank you so much, Posse,
• 46:23for really a fantastic talk.
• 46:26It was so clinically relevant
• 46:28and you're doing amazing work
• 46:30to really advance this field.
• 46:31So thank you again for all
• 46:32of that and for being here.
• 46:34So as is tradition,
• 46:35the first question goes back
• 46:36to Vito Calabrese. I don't
• 46:41know. All right. OK.
• 46:42Additionally, I asked a first question,
• 46:44even if I have nothing to say.
• 46:47But I was wondering whether in other
• 46:51types of cancers like Melanoma which
• 46:54got treated from nothing and then had
• 46:58the same intermediate stage developed
• 47:01where there were some cells of this
• 47:03sort and they found ways of going
• 47:05after them or whether there there was a
• 47:08total treatment from the first time. So
• 47:13depends a little bit on the type of therapy.
• 47:15But this sort of intermediate state
• 47:17does exist in other cancers if they're
• 47:19especially if they're treated with the
• 47:21targeted therapies that I mentioned.
• 47:23I think the difference in
• 47:24Melanoma is that it's a very,
• 47:26it's a cancer that we can effectively
• 47:29treat with immune therapies that
• 47:31are already exist and were developed
• 47:33in Melanoma and other cancers.
• 47:35They do work in lung cancers as well.
• 47:37They just don't work in the lung cancers
• 47:39that have these genetic alterations
• 47:40where we use these targeted therapies.
• 47:42And so that's why we need
• 47:44different approaches.
• 47:45But it isn't this example.
• 47:46This sort of pattern isn't
• 47:48unique to lung cancer,
• 47:49does happen in other cancers as well.
• 47:53Hi, I'm. I'm Steve Calabresi, Dr.
• 47:56Calabresi's son. And I'm a law professor.
• 47:59So this question may not be
• 48:01thoroughly relevant, but my father
• 48:05had a cancer of the tongue in 1975
• 48:09on the left side of the tongue and
• 48:12was given a 15% chance of surviving.
• 48:15He ended up living another 25 years.
• 48:17The way he treated the cancer of the
• 48:20tongue was to have surgery on his
• 48:23tongue and to have the glands on
• 48:25the left side of his neck removed,
• 48:28which turned out to have cancer
• 48:30cells in them. He had chemotherapy,
• 48:33He had radiation therapy with
• 48:35radioactive needles in his tongue,
• 48:37and he even used, in 1975,
• 48:40a primitive form of immunotherapy.
• 48:43And his idea was to throw everything,
• 48:45everything at it, basically.
• 48:47And so I wondered with these
• 48:50persistent can cancers,
• 48:51can you once you reduce the size of
• 48:53the cancer to a smaller location,
• 48:56is there any chance of gaining
• 48:58anything by surgically removing it.
• 49:00Obviously microscopic cancer cells
• 49:02might remain but maybe those would
• 49:04could be targeted by chemotherapy or
• 49:06yeah so in in the,
• 49:07in the EGFR example and Roy knows
• 49:10is very well since he led the the,
• 49:13the, the trials patients who have
• 49:15earlier stage lung cancer which we
• 49:18can potentially cure with surgery
• 49:20although it can still recur.
• 49:22We now use these effective like the
• 49:25the EGFR inhibitor as an adjuvant.
• 49:28So after surgery patients may get
• 49:30chemotherapy and then they get the EGFR
• 49:32inhibitor for multiple years there.
• 49:34We know that that not only reduces the
• 49:38likelihood of the cancer coming back,
• 49:40but it makes people live longer.
• 49:43Now whether whether it ultimately
• 49:45cures those cancers,
• 49:46I think we don't know yet,
• 49:47but at least the early signs are
• 49:49all going in the right direction.
• 49:52So yes,
• 49:53absolutely we're trying trying to
• 49:56take what we learn in studying
• 49:57patients with advanced lung cancer
• 49:59and moving the effective therapies
• 50:01into earlier settings where we can
• 50:03hopefully cure more patients with
• 50:04the with the disease as as long
• 50:06as we can find the the cancers in
• 50:08the earlier stage which remains
• 50:09a challenge still
• 50:13really nice talk. I'm wondering if
• 50:15drug therapy is acquired through
• 50:17somatic mutations or if there are
• 50:20pre-existing cells that then
• 50:22grow out that account for the.
• 50:25Yeah, both can happen and there's
• 50:27and and and and certainly there are
• 50:29examples in lung cancer and then
• 50:31EJFR space where you can find the,
• 50:34you know, you know one in a million
• 50:36cells you can find the resistance
• 50:38mechanism cancer with a resistance
• 50:40mechanism already there and then
• 50:43over time it gets selected for.
• 50:46But the other way around,
• 50:48the other other is also true
• 50:50that you may not find it,
• 50:51but it's this intermediate state for
• 50:54whatever reason then is denied us for many
• 50:57different resistance things to evolve,
• 50:59and part of the reason to
• 51:01to of course go after that.
• 51:03But both do exist.
• 51:05Both both paths to resistance are possible.
• 51:08Doesn't mean they can't coexist either.
• 51:15Hi, Pasi, it's good to see
• 51:17you and thanks for coming.
• 51:18It's beautiful work.
• 51:20I wondered if in the studies
• 51:22that you use the combination of
• 51:25your BCLXADC and ASA Mertonib,
• 51:27did you add, did you do any
• 51:29studies combining that with the
• 51:30MEC inhibitor because it looks
• 51:32like that's your preclinical
• 51:33data with support that triplet.
• 51:35Yeah, We we didn't, we didn't.
• 51:37And part of it is that it's,
• 51:39it's tough to take the MEC inhibitor
• 51:42combinations forward clinically
• 51:43because of the MEC inhibitor toxicity.
• 51:45And so we wanted to stick to strategies
• 51:49that we could ultimately test in the
• 51:51clinic in the form of a clinical trial.
• 51:54And as you said,
• 51:55we're doing a trial of ASA,
• 51:56Merton and Ben Celimetin,
• 51:58but even that and even giving it an
• 52:01intermediate or intermittent dose levels,
• 52:03not everybody can tolerate it.
• 52:05The MEC inhibitor toxicity adds up over time.
• 52:10Thanks.
• 52:12I'm going to ask a question
• 52:14as I walk over here POSI.
• 52:15I think you know one of the studies
• 52:17that I was really struck by is the
• 52:19the study that you did where you
• 52:21buy up did on treatment biopsies.
• 52:22I think it's something we a lot of
• 52:25trials have them as optional biopsies
• 52:26and I think sometimes we feel it's hard
• 52:28to to have patients go through that.
• 52:30I'm just curious your experience in
• 52:32the clinic because it's such important
• 52:33samples how how it was talking to
• 52:35patients about that and getting those
• 52:37samples and the importance of those
• 52:39most most patients that this
• 52:43trial and other trials as you
• 52:47mentioned require on study biopsies.
• 52:49And I think we're most of our patients
• 52:53are willing to assuming it's safe and
• 52:56the tumors in a location that can be
• 52:58biopsied are willing to undergo that.
• 53:00You know after we explain to them and you
• 53:04know although it may not help them directly,
• 53:06it'll help the development of medicines
• 53:08that we're trying to develop and
• 53:10it'll help others in the future and
• 53:12we do we we are have been able to
• 53:14be successful in that but it is it,
• 53:17it is optional in most cases
• 53:20optional typically means not done.
• 53:22So so yeah it it remains a challenge
• 53:27a really great talk
• 53:29as a radiation oncologist.
• 53:30One thing I worry about is,
• 53:31is there evidence of the senesa state
• 53:33being more or less ready resistant
• 53:35initial tumor and clinically it might
• 53:37be relevant patients got you know
• 53:39a handful of brain Mets and right
• 53:40now if they have an EGFR option
• 53:41do we do radiosurgery upfront,
• 53:43do we just do EGFR therapy and then
• 53:45watch wait for it to come back.
• 53:46When's the right time to kind
• 53:47of incorporate
• 53:47right. And there there there is,
• 53:49there are studies that are looking
• 53:50at this you know for EGFR therapies,
• 53:53you know patients who have sort
• 53:55of maximal response radiating the
• 53:57sort of the remaining areas and and
• 53:59and there are some studies that
• 54:00suggest that that may be beneficial.
• 54:02And we typically have a radiation
• 54:07oncologist see our patients have
• 54:08that they've had a maximal response
• 54:10to whatever targeted therapy to
• 54:11ask is it feasible,
• 54:12is it in a location that can
• 54:15you know that that is can be
• 54:17done in terms of brain lesions.
• 54:22I think as medical oncologists
• 54:24we prefer to have pharmacologic
• 54:26approaches to treat brain lesions,
• 54:28although we rely heavily on our
• 54:30radiation oncology colleagues
• 54:32for stereotactic radiation.
• 54:33But if we can avoid things like
• 54:35whole brain radiation with
• 54:36using pharmacologic agents,
• 54:38I think that would be preferable.
• 54:40But not all of our agents as you know
• 54:43across the blood brain barriers.
• 54:46Posse, thanks so much for
• 54:47being our visiting professor.
• 54:48As you know as well as anyone,
• 54:49it's now 20 years since the EGF
• 54:51reputations were discovered.
• 54:52Your lab was of course one of
• 54:54the key labs in that and it's so
• 54:56tantalizing to have these oral
• 54:57agents and patients live longer.
• 54:59But as you mentioned,
• 55:00no one's ever really cured.
• 55:02So now you've described to us adding
• 55:03different agents in that add toxicity.
• 55:05So my question is going to be
• 55:06about that it really does change
• 55:08the course of a patient's life as
• 55:09you start adding in some of these
• 55:11toxicities with you have to come in
• 55:13for intravenous infusions exactly.
• 55:14So my specific question is going to
• 55:16be something we're interested in here,
• 55:17some of the the pulmonary toxicity we
• 55:19see with these antibody drug targets.
• 55:21Is there anything that's known
• 55:22about structure function and will
• 55:24there be ways to ameliorate that?
• 55:25Because certainly you take
• 55:27someone with a long life span,
• 55:28but you if they end up having
• 55:29a pulmonary crisis that could
• 55:30be of course very devastating.
• 55:32Yeah. I don't think we as a field
• 55:37completely understand why some of
• 55:39these antibody drug conjugates
• 55:41give a rise to pulmonary toxicity.
• 55:44Or of course it is the the, the one of
• 55:48the more feared toxicities because A,
• 55:52that can be symptomatic and B typically
• 55:54means you have to stop using that treatment,
• 55:56even though if it's if it's been
• 55:58effective because you don't want to,
• 56:00you know, make the toxicity worse.
• 56:01But our mechanistic understanding of
• 56:04what gives rise to that I think is at
• 56:07its infancy still and I think something
• 56:10that we should continue to work on.
• 56:12And they're not great models like mice don't
• 56:16get interstitial lung disease from that.
• 56:18So you have to have a good
• 56:19model to be able to study in.
• 56:22I think we have time for one and
• 56:24maybe two questions. So just
• 56:25my question come from pathology NGS,
• 56:28so this persistent cells.
• 56:29So when we get that tumor treated
• 56:31and recurrent, we see additional
• 56:33mutation in GFR amplification,
• 56:35some tumor exchange to become
• 56:36neuron decrin and squamous.
• 56:38These persistent tumor cells where
• 56:39they are located in in these pathways
• 56:44typically as I showed you pre
• 56:46clinically typically if we take
• 56:48one of these persistent
• 56:49cells and do NGS on them,
• 56:50they don't have any other genetic
• 56:52alterations compared to the parental
• 56:54because they're basically just
• 56:56rewired to be able to survive.
• 56:58And if you in that preclinical
• 57:00experiment if you take off the drug
• 57:02they regrow and they're the signaling
• 57:04pathways look like look the same
• 57:06as they do in the parental cells.
• 57:08So it's it's it's sort of an adapt,
• 57:11it would fall under sort of an
• 57:13adaptive resistance that allows
• 57:15survival but not necessarily driven
• 57:17by a specific genomic mechanism. OK,
• 57:21David, I think this will
• 57:22be the last question from pathology.
• 57:26So the protein expression of
• 57:28both trope 2 and EGFR spans
• 57:30about a two log dynamic range.
• 57:32Have you ever looked at the levels
• 57:34of protein expression to correlate
• 57:35with your ADADC effects that you see?
• 57:37So clinically that's been looked
• 57:40at and disappointingly has no
• 57:43correlation with the efficacy of
• 57:45Trope 2AD CS or her three AD CS.
• 57:47Now maybe it's because we don't
• 57:50have the right assets to look at.
• 57:54Maybe it's because other things you
• 57:57you need the expression of the target,
• 57:59but you need other things.
• 58:00The antibody has to bind the target.
• 58:03It has to be internalized.
• 58:04It has to be transported to the right
• 58:06cell compartment where then the the,
• 58:08the the conjugate is cleaved and and
• 58:10and then can kill the tumor cells.
• 58:13So maybe maybe there are other things
• 58:15that are important in that in that
• 58:17overall efficacy as well not just the
• 58:19expression of the of the of the target.
• 58:24Great. Well possibly.
• 58:26Again, thank you so much for really a
• 58:28fantastic talk and for coming to visit.
• 58:30I will just make one announcement
• 58:32which is after this in the next
• 58:33couple minutes we're going to gather
• 58:35outside and and the fellows and
• 58:37other trainees are going to have a
• 58:38chance to ask you more questions and
• 58:40really look forward to that as well.
• 58:42Thank you again.
• 58:44Thank you.