Targeting Apoptosis in Leukemia:lessons and challenges

Transcript

• 00:00Good morning, everyone.
• 00:01Thank you so much for coming.
• 00:04It's really a true pleasure today
• 00:06to have with us one of the gents
• 00:08of acute myeloid leukemia and
• 00:11myeloid neoplasms in general.
• 00:12So Doctor Marina Konopoliva is
• 00:15a professor in the Department of
• 00:17Oncology and Molecular Pharmacology
• 00:19and the Merriam Faculty Scholar
• 00:22in Cancer Research at the Albert
• 00:24Einstein College of Medicine.
• 00:26After spending many,
• 00:27many years in the Andy Anderson,
• 00:29where she has really made
• 00:31fantastic contributions,
• 00:32including very important drugs
• 00:34that have been approved both
• 00:36in acute myeloid leukemia and
• 00:39plastic denritic myelo neoplasm.
• 00:42So she received her Doctor of Medicine
• 00:45from the First Pavlov Medicine
• 00:47Institute in Saint Pittsburgh in Russia,
• 00:50and then got a PhD in experimental
• 00:53hematology from the Federal Institute
• 00:55of Hematology and Blood Transfusion.
• 00:57So Doctor Konopliva's research
• 00:59has focused on patients with
• 01:01hematologic malignancies both
• 01:02including acute myeloid leukemia,
• 01:04acute lymphoblastic leukemia
• 01:05as well as high risk MD's.
• 01:08And her research,
• 01:10as I mentioned,
• 01:11have led to important not only
• 01:13science and advancing,
• 01:15but also therapeutic translation,
• 01:17especially venetoclax,
• 01:18which really has changed the landscape
• 01:21of how we treat patients with the AM, LCLL,
• 01:25potentially MD's and other conditions.
• 01:29And on a personal level,
• 01:31I think Doctor Konopleva is very known
• 01:32in the field to be a fantastic mentor.
• 01:34She has mentored some of the most
• 01:37productive researchers in the field
• 01:40as well as being a very nice and
• 01:42very good person to interact with.
• 01:44So I encourage as many of you to
• 01:46talk to her if you can today.
• 01:47Thank you so much for coming.
• 01:55Thank you, Amir,
• 01:56for this very kind introduction.
• 01:57I'm happy to be here.
• 01:58This is my first time at Yale
• 02:00and I'm looking forward for the
• 02:02day and meeting a lot of you.
• 02:04And so today I wanted to take
• 02:07you through our story on Biso 2.
• 02:09I know this is like a general grand
• 02:11round for both human solid malignancies,
• 02:13but I think targeting cell death is
• 02:16probably important for including
• 02:17for the solid tumors as well.
• 02:19And I'll show you some of the kind
• 02:20of ways we think about that as well.
• 02:25So these are my disclosures and as
• 02:28you all know, the resistance to cell
• 02:30death is one of the hallmarks of cancer
• 02:33and it's largely governed by the B22
• 02:36family proteins which are listed here.
• 02:38It's quite complicated.
• 02:39I'll show you later how the system works,
• 02:42but essentially there's over
• 02:44expression of different B22 family
• 02:46members depending on the tumor type.
• 02:48For example in myeloid malignancies
• 02:51and we have mainly B so 2IN TALL.
• 02:54We also have B cell XL and B so two
• 02:56and M So one is kind of ubiquitous
• 02:58and I think in SO2 must B cell XL is
• 03:01a primary anti apoptotic molecule.
• 03:04The way the system works is by
• 03:06dimerization of anti apoptotic with a
• 03:09propoptotic family members and there are
• 03:11quite a few of those as well So bags.
• 03:14I will talk to you several times in my talk.
• 03:17So this is what we call execution
• 03:19of cell death protein.
• 03:20So essentially kills the cells by making
• 03:22pores in the mitochondria membrane
• 03:24and inducing cytochrome C release.
• 03:27And then there are a lot of this will be A
• 03:29share only proteins which essentially bind B,
• 03:31so two or others and inhibit their function
• 03:34because it works through demoralization.
• 03:36You can actually inhibit the function
• 03:38of B so 2 by inhibiting the protein
• 03:42protein interactions between for
• 03:44example B so two and some of this
• 03:47protest proteins and as a result you'll
• 03:49have a release of this propagatoric
• 03:51members and killing of the cell deaths.
• 03:54So this was pioneered in the first attempt.
• 03:58This was a paper back in 2005.
• 04:01At the time the company was called Abbott
• 04:04and they designed the first protein
• 04:07protein inhibitor which was called Abt 737.
• 04:10So this was a work from Steven,
• 04:12Fasig,
• 04:12Sol Rosenberg and others that
• 04:15effectively inhibited the BCL two.
• 04:17So the structure here is
• 04:19actually the structure of BCL XL.
• 04:21So they used the NMR based technology to
• 04:24engineer this molecule and green protein
• 04:26here is one of this proteins called back.
• 04:30It's not even here but it's one of the BHA.
• 04:33On your proteins there's some critical
• 04:35critical rates reduced how it binds
• 04:37to B cell XL and this is the actual
• 04:39molecule which you can see it sits
• 04:41into that pocket and this mimics the
• 04:44B back interaction with B cell XL.
• 04:47In this matter there's another structure,
• 04:50this is pretty large molecule about
• 04:53960 KD but this was the 1st and I
• 04:56think the most successful protein
• 04:58protein inhibitor interaction.
• 04:59I think the only other class that I'm
• 05:02aware of MDM 2P53 inhibitors but they
• 05:04still not approved due to toxicities.
• 05:07Now this molecule was A2 molecule
• 05:10and it's analogue called Navidoclax
• 05:12did go into clinical trials,
• 05:15but because it blocked both BCL
• 05:17XL and BCL two,
• 05:18it encountered some toxicities in the
• 05:21form of thrombocytopenia because BCL
• 05:23XL is important for plated production.
• 05:26But I'll get back to you in the end.
• 05:27I think BCL XL targeting is very
• 05:29important and there
• 05:31are other ways of safely inhibit BCL XL.
• 05:33So Nabilox is still not approved.
• 05:36And so moving forward in 2013,
• 05:40the same company now it's called Abbi
• 05:42engineered the original molecule and
• 05:45they got rid of BCL XL interaction.
• 05:48So apparently this aspartate one
• 05:50O 3 is a critical residue which is
• 05:53different between BCL two and BCL XL.
• 05:56And so they engineered the new
• 05:58molecule that had now very specific
• 06:00BCL two only properties.
• 06:01So it only bound BCL two was about
• 06:0410 times more important than original
• 06:06nebidoclax and it did not inhibit BCL XL.
• 06:10And this is what we now know
• 06:12as the neto clocks,
• 06:14the drug that is approved for several
• 06:16types of hematologic malignancies.
• 06:18And of course it's paid playlists
• 06:20because it did not inhibit B cell XL.
• 06:22So I said I work on B.
• 06:24So too when I came to us,
• 06:26that was my first project at the time.
• 06:28We initially used the antisense,
• 06:29but antisense didn't make it in clinic.
• 06:31They were not effective enough,
• 06:33not specific enough.
• 06:34And then when the original
• 06:36camp compound came out,
• 06:38we developed the story on
• 06:40AML and BCO 2 with ABT 737,
• 06:43which were published in 2006.
• 06:45And then when the new compound came out,
• 06:48because Nevada clocks never
• 06:49made it to AML trials,
• 06:51again,
• 06:51AML patients as you know have
• 06:53all low platelets to start with.
• 06:55So it was kind of impossible at the
• 06:57time to transition into AML trials.
• 07:00When the newcomer came out,
• 07:01we teamed up with a Tony Litais lab
• 07:03at Denif Harbor and we worked for
• 07:05a year between two of our labs and
• 07:08published a cancer discovery paper
• 07:10in 2014 showing that the Nanoclax is
• 07:12highly effective in acute myeloid
• 07:14leukemia pre clinical studies.
• 07:16So,
• 07:16so these are just I'm not going
• 07:18to go through the paper or data
• 07:20that's all published,
• 07:21but these are just mRNA level for B,
• 07:24so two amongst different types of
• 07:26leukemia and the red line represents
• 07:28to the normal uninvolved bone marrow.
• 07:31This was from a Hyperlux MLL collection.
• 07:34So you can see that majority of
• 07:36AML this is log scale have upper
• 07:38related mRNA for BC2.
• 07:40There's some examples here,
• 07:41some some some that don't.
• 07:43For example this inversion 3 AML do not,
• 07:45but majority have high levels of BC two.
• 07:49We also show that it's expressed
• 07:51on leukemia stem cells and then
• 07:53we show that if you target BC two,
• 07:55you eliminate AML blasts and AML
• 07:57stem cells to some extent.
• 08:00And also the compound had efficacy in vivo,
• 08:02although by itself it,
• 08:03it was not curative and it wasn't
• 08:06curative in patients either.
• 08:07So this work in conjunction with
• 08:11the CLL data that Amar mentioned.
• 08:13So that time the Netflix was already
• 08:15in CLL trials and was very effective.
• 08:18It caused tumorlysis and actually they
• 08:20had some deaths because of tumorlysis.
• 08:22So it's CLL is super dependent on B, so true.
• 08:25So it's like the primary B,
• 08:27so two dependent disease,
• 08:28but we already knew the dose,
• 08:31we knew the safety profile of
• 08:33this molecules was fairly safe
• 08:35besides this tumuliser syndrome.
• 08:37So it was sort of sufficient based
• 08:41on this work to take venetoclax
• 08:43into AML relapse refractory study.
• 08:46So this study was conducted between
• 08:49different institutions and was published
• 08:52in cancer discovery back in 2016.
• 08:54So initially we projected that we're
• 08:57going to treat 50ML patients and we
• 08:59were hoping for response rate around 40
• 09:02to 50% based on our preclinical work.
• 09:05And I have to say that this did not pan out.
• 09:07So we learned that AML is way too
• 09:09complicated and probably our preclinical
• 09:11models do not really faithfully
• 09:14recapitulate the response in in patients.
• 09:16So the response rate,
• 09:18objective response rate in the trial
• 09:19was only 19% with the CRCRI rates,
• 09:23but about 50% of patients did
• 09:26have blast reductions as shown
• 09:28here on this waterfall plot.
• 09:30And then there were some subsets of patients
• 09:32who tend to be more sensitive to that.
• 09:34For example,
• 09:35patients who had IDH 1-2 mutations,
• 09:37they generally had response and the
• 09:40response among those was about 32%.
• 09:43So that was encouraging.
• 09:45And in fact,
• 09:46we enriched the study for the IDH
• 09:481-2 mutated patients because at
• 09:50the same time the paper came out
• 09:52from Stanford showing that this
• 09:54subset of AML is highly be so
• 09:55dependent and that turns to be true.
• 09:57Till now this patients respond very
• 09:59well to nine, 8:00 to 9:00, sorry,
• 10:02but essentially that was encouraging,
• 10:05but it was clearly not enough for
• 10:06to get this drug approved as a
• 10:09single agent in the salvage setting.
• 10:11And of course for me as a researcher
• 10:13that was disappointment because I
• 10:15thought this was like the best drug
• 10:17I ever had in the lab and still
• 10:19it's not you know curing people.
• 10:21The duration of responses was also
• 10:23pretty sure about three to six months
• 10:25and all patients progressed after that.
• 10:27So fortunately the story did not
• 10:29stop at this point as you know.
• 10:32And so why we think that AML
• 10:35in AML target and B,
• 10:36so two alone is not sufficient?
• 10:39Well,
• 10:39first of all,
• 10:40because there's a redundancy and
• 10:41expression of BCL two family proteins.
• 10:43So if you just look at this western blood,
• 10:45this is from Andrew Ways publication
• 10:48and BCL two is almost ubiquitously
• 10:50expressed at high levels.
• 10:52BCL XL is usually not expressed
• 10:55or low expressed.
• 10:56But I'll tell you which subsets
• 10:58do have BCL XL And then there's
• 11:01MCL one which is mildly specific
• 11:04sort of BCL two family member,
• 11:06it's ubiquitously expressed as well.
• 11:09So you can imagine that if
• 11:11you target only be so true,
• 11:13you leave some other members untouched
• 11:16and therefore cells probably quickly
• 11:18adapt to the this effect and they
• 11:21rewire and they become resistant.
• 11:23So how can you get around that?
• 11:25So the next thing is that any
• 11:27type of chemotherapy can actually
• 11:29in the setting of wild type B53
• 11:32can induce expression of this
• 11:34proprietoric family members that
• 11:36I mentioned before what we call BHA
• 11:38only proteins and this PH3 only
• 11:40proteins can in fact inhibit MCO one.
• 11:43So as you can envision,
• 11:46you can have synergy between
• 11:48venetoclax and pretty much any type
• 11:50of chemotherapy that would induce
• 11:52this response and then you inhibit B.
• 11:54So two, so you sensitize the
• 11:56cells and then there's bags back
• 11:58interaction and the cell death.
• 12:00So practically speaking this went into
• 12:02development in all the AML patients
• 12:05unfit for chemotherapy because for
• 12:07younger patients we had 7 + 3 which
• 12:10we still have and they were doing
• 12:11pretty well with the transplant.
• 12:12But for all the patients there was
• 12:14really like no standard of care
• 12:16low dosa turbine or hypermethylene
• 12:18agents have been used.
• 12:20So I have to say that based on the
• 12:23clinical need more than the signs,
• 12:25the combination trials were with
• 12:27hypermethylene agents and low dose
• 12:29Iturbin and all done fit there
• 12:31for chemotherapy AML patients.
• 12:33And this were the results of the
• 12:35initial Phase 1B study when the
• 12:37Vanetta glass was combined either
• 12:39with azacitidine or with a decitabine,
• 12:42hypermethylene agents or even with
• 12:44low dose Iturbin which by itself
• 12:47has very little activity in AML.
• 12:49And you can see here that well you know
• 12:51this was a newly diagnosed patients.
• 12:53So was very rapidly was transitioned
• 12:55to the newly diagnosed CML which I
• 12:58think was another difference with
• 12:59the original trial that we used
• 13:01where we used phonetically where
• 13:02it was relapsed refractory setting.
• 13:04But you can see that you know majority
• 13:07of patients in fact responded and
• 13:10they did achieve like true CRS.
• 13:12There was some of those escalation
• 13:14findings as well,
• 13:14but eventually 400 milligram ended
• 13:16up the right dose for the HMA
• 13:19and 600 for the low dose,
• 13:21high turbine combination.
• 13:22So the responses,
• 13:24the responses tend to be durable
• 13:25and there was very little toxicity.
• 13:28So suddenly the all the patients
• 13:30which for which we didn't really
• 13:32have QS before in one month
• 13:34that we're going into remission,
• 13:36the infections and mouse suppression
• 13:37was still the main toxicity.
• 13:39But other than that we didn't see
• 13:41like much effects on the kidney,
• 13:42liver or anything which was to me always
• 13:45the most surprising thing because B
• 13:47so two is so ubiquitously expressed.
• 13:49So who could imagine that
• 13:50targeting B so two is so safe.
• 13:52I think before we go into clinic,
• 13:54we can never really predict what happens.
• 13:57And then eventually this resulted
• 14:00in the randomized phase three study
• 14:03called VLA study where VENESA,
• 14:05what we call venetocide was randomized
• 14:08to azacide and placebo control.
• 14:11It was 2 to 1 randomization and
• 14:13this was for all the patients with
• 14:16AML ineligible for chemotherapy.
• 14:18The median age was close to 70
• 14:21years old and you can see that
• 14:23there's far as response rate,
• 14:24majority of the patients achieved
• 14:26response it was which was
• 14:28in the range of 60 to 70%.
• 14:30There was lower in PPG mutated
• 14:32AML which we learned later is a
• 14:35a prom for this approach.
• 14:36But overall there was high response rate,
• 14:39but most important there was survival
• 14:41advantage compared with ASA with medium
• 14:44overall survival of about 14 months and
• 14:46compared to nine months with ASA cited in.
• 14:49So this LED in 2018 to the accelerated
• 14:53approval of the Naglo X and AML and
• 14:56subsequently to the full approval in
• 14:58combination with the chemotherapy
• 15:00low Dosa turbine is also approved.
• 15:02But even though they missed
• 15:04the primary endpoint,
• 15:05but the overall survival was still better.
• 15:07But I think it's very rarely used
• 15:10in United States and this survival
• 15:13is shorter only about nine months.
• 15:15So this is like what Amar said is
• 15:18considered to be breakthrough.
• 15:19But you know if you look at the curves,
• 15:21you can say that is this really like
• 15:23a breakthrough because majority of
• 15:25the patients are still you know,
• 15:27dying from their disease.
• 15:28Initially it seemed to be like
• 15:30plateau here at 30%.
• 15:31So now the curve dropped down to about
• 15:3420 to 25% with about four years of follow up.
• 15:36So it still stands,
• 15:38but clearly you know it was not a
• 15:42curative approach and that kind of
• 15:44prompted our lab and many other groups
• 15:46going back to the kind of drawing
• 15:48board and trying to understand how
• 15:50we can improve on that and what are
• 15:53mechanisms of resistance and how
• 15:55we can combine with other agents.
• 15:57So in the rest of my talk,
• 15:58I will show you like several like
• 16:00examples from our lab how we kind of
• 16:02developed the new agents for the combination.
• 16:04Some of them are in trial,
• 16:06some of them are hopefully getting to
• 16:09approval soon and this is sort of a
• 16:12summary how we can think of potential
• 16:15combinations and resistance mechanisms.
• 16:17This figure was done by one of our
• 16:20fellows and again going back to
• 16:21like how the drugs work, right.
• 16:23So again you have BSO 2,
• 16:25you have it pre complex with BHA
• 16:27only protein which allows you to
• 16:30block this interaction.
• 16:31And this is a drug venetoclax,
• 16:33it's called BHA mimetic because
• 16:35it mimics PHA only proteins.
• 16:37So it binds here,
• 16:38it displaces this BHA only and then this
• 16:41products have to activate backs and back.
• 16:44So again backs and back are very
• 16:46critical because without that there's
• 16:48no cell death and they have to go
• 16:51into the mitochondrial membrane
• 16:52and they induce sacrum C release.
• 16:55So one thing that I already
• 16:57mentioned that there's a redundancy,
• 16:58so if you have a regulation of
• 17:00this other B SU-2 family members,
• 17:03you can get resistance right?
• 17:05Because they can even though you
• 17:06do have displacement,
• 17:07what happens is that this BHA only
• 17:10protein instead of going to the bags it
• 17:12will go and bind this other protein members.
• 17:15So how can you get this app regulation?
• 17:18Of course it may have
• 17:20been before pre-existing.
• 17:21For example in monostatic AML there's
• 17:23app regulation of MCL one because of
• 17:26the lineage dependency on MCL one.
• 17:28But then there are a lot of
• 17:30mutations and this
• 17:30mutations we call them signalling mutations
• 17:33which we now can up regulate both MCO one,
• 17:35BCL XL and BCL 12A1 and I'll
• 17:38show you some examples of those.
• 17:40So this will lead to resistance
• 17:42and of course you might want to
• 17:44think of targeting those mutations.
• 17:46So the other major mechanism of
• 17:48resistance is the P53 loss and I
• 17:50already mentioned that PhD is critical
• 17:53for BHA only proteins induction.
• 17:55But on top of that P53
• 17:57transcriptionally controls Bax,
• 17:59so BAX levels are lower and P
• 18:03and P3 lost AML and there's also
• 18:05other mechanism of resistance.
• 18:06So this remains unmet need
• 18:09in the field of AML and MD's.
• 18:12And then there are some other mechanisms.
• 18:15For example,
• 18:16Yanis offenders group has published
• 18:18the mitochondria resistance to the
• 18:21venetoclax through our regulation of
• 18:23some of this crystal proteins such as
• 18:25Glib B and also mitophagia kind of
• 18:28selection of the healthy mitochondria.
• 18:31And there's some effort as far as
• 18:34drug discovery in that field as
• 18:36well going back to the patients.
• 18:37So what did we see like from this mechanisms?
• 18:40What did we see as far as the
• 18:43resistance development?
• 18:44And before that I have to say that we
• 18:47also developed in the lab habanero clocks,
• 18:50resistance cell lines.
• 18:51So we decided to take some of
• 18:53unbiased approach and we generated
• 18:554 vein resistance cell lines.
• 18:58They're available for anyone who
• 19:00wants to use them by prolonged
• 19:02exposure to the drug in the tissue
• 19:04culture lab and took only about
• 19:063 months to generate the cells.
• 19:07So about the same time as our
• 19:09patients to progress.
• 19:10And then we did all kind of metabolomic
• 19:13genomic proteomic profiling and
• 19:17epigenetic profiling as well.
• 19:18So one pathway that came out kind of
• 19:20screaming at us, which was not a new pathway,
• 19:23but it was something that we already
• 19:25knew from before.
• 19:26It was MEP kinase pathways.
• 19:27So it was upregulated on the RNA level.
• 19:30And then we confirmed that in
• 19:32the by immuno blotting analysis,
• 19:34you can see application of some of
• 19:36this MEP kinase pathway proteins
• 19:38and as a result MEP kinase can
• 19:41stabilize MCL one proteins.
• 19:44So it's not transcriptional but on
• 19:45the level of the protein and we did
• 19:47see that in all the three cell lines
• 19:50M so one levels were up regulated
• 19:52as you would expect And then if you
• 19:54use the either M so one inhibitors
• 19:56or knockout of M so one you get
• 19:59tremendous synergy with venetoclax
• 20:00and the cells are are dying off.
• 20:03So I'm not going to talk about M
• 20:04so one inhibitors but suffice to
• 20:06say that they are not approved
• 20:08because of toxicity.
• 20:09So again like thinking why B so two so
• 20:11safe and M so one is not safe so M so one.
• 20:14Tends to be very important for the heart
• 20:17muscles and so patients treated on the
• 20:19clinical trials with MC1 inhibitors,
• 20:22they have what we call Troponin leak and
• 20:24potentially you know cardiac toxicity.
• 20:26So that Hanford the whole like
• 20:29development of MC1 inhibitors
• 20:30and it's not clear whether they
• 20:33actually have therapeutic windows.
• 20:34So, but in the lab, these are the
• 20:38great sensitizers to Vanadacolexa.
• 20:40So then we went back to patients and
• 20:42we know that in patients Ras mutations
• 20:44are fairly common in AML on their own.
• 20:46They don't have prognostic significance,
• 20:48but they can arise at the
• 20:51time of progression.
• 20:52And so when we looked at the patients
• 20:54treated on the HMA venetoclax
• 20:56trials at the time of relapse,
• 20:58they had like expansion of this Ras, K,
• 21:01Ras and Ras clones also PTPN 11 clones,
• 21:05which is not shown here fairly
• 21:07quickly within like 6 months or so.
• 21:09This has single cell DNA sequencing data.
• 21:13We also looked at the sort of
• 21:15patients by immunoblotting.
• 21:16So we did show up regulation of
• 21:18MCL one and the approgation of
• 21:20MAP kinase pathway and this is
• 21:21on the histochemistry level.
• 21:23At the time progression MCL one was
• 21:26up and BCL two was down regulated.
• 21:28The problem of course that in
• 21:30AML we don't have Ras inhibitors.
• 21:32We are really hoping that we can
• 21:34get them from the solid tumors.
• 21:36But the companies have been so
• 21:37focused on the lung cancer and they
• 21:39have been reluctant to go into AML.
• 21:41So we are still trying to convince
• 21:44them that Pan Ras inhibitor would be
• 21:46a great thing to have an AML and we
• 21:49actually have data with the in the lab
• 21:52that the combination is really striking,
• 21:54the papers submitted.
• 21:55But right now we don't have anything.
• 21:58So we also did the engineer this in the lab.
• 22:00So we put the NRAS G12D into AML
• 22:04cell line which was dox inducible.
• 22:07We showed that the cells become
• 22:09resistant to another clocks.
• 22:10But again the MCL one inhibitors
• 22:12work alone on combination.
• 22:14We did the mouse study with MCL
• 22:161 inhibitors and there was a
• 22:17reduction of the tumor growth,
• 22:19but we don't have MCL 1 inhibitors
• 22:20and we don't have resin inhibits.
• 22:21So we are like at a loss right now,
• 22:24but we're working on that.
• 22:27So this MEP kinase upregulation I
• 22:28think is one of the major kind of
• 22:31resistance when you use HMA Van.
• 22:34It's not an issue when you use chemotherapy,
• 22:36van,
• 22:36because Rascalone is very sensitive
• 22:38to the regular chemotherapy,
• 22:39which is kind of a relief.
• 22:42And this data we have sort of confirmed
• 22:44that this was a large analysis.
• 22:46I think the paper is under review from Viali,
• 22:49a study looking at different genomic
• 22:51subsets of patients who are and time to
• 22:54progressional this is rather survival.
• 22:57This was presented at by Hartman
• 22:59donor at the last ASH.
• 23:01And so they basically show that the
• 23:03classical kind of ELN classifications
• 23:05do not predict very well the
• 23:07response or duration of response.
• 23:09But when they did looked at
• 23:12different genomic subsets,
• 23:13again P50 mutated AML did very poorly.
• 23:16So survival was only about 5 months here,
• 23:19same as you get with HMA.
• 23:21But this intermediate cohort,
• 23:23it actually included patients with Ras
• 23:25mutations. So Ras mutation was confirmed
• 23:27to be like resistance factor for the HMA
• 23:30band and also another mutation signaling
• 23:32mutation F FLIX free FLIX free ITD mutation.
• 23:36So this data are being sort of refined that
• 23:38I told you a little about the Ras story.
• 23:41Now Flix 3 is another very common mutation,
• 23:43about 30% of patients have Flix 3 mutation.
• 23:46Unfortunately we have drugs for
• 23:48those that are being approved.
• 23:49So of course like we jumped into that
• 23:52very early on and in fact we saw that
• 23:54even in the original phase one study
• 23:56where which showed up regulation of
• 23:58this or selection of the clones with
• 24:00the Flix 3 IT do or as mutations and
• 24:03people who relapse or wear primary
• 24:05fracture and very similar this like
• 24:07selection of the Flix 3 ITT clone with a
• 24:11therapy using the single cell tapestry
• 24:13sequencing and the sort of why Flix 3
• 24:16ITT the story is very similar to Ras.
• 24:18So here you have you know the
• 24:20same Ras map kindness pathway.
• 24:22You also have a prolation of some other
• 24:25ones that five PS3 kines AKT but eventually
• 24:27it all comes down to this MCL one.
• 24:30So MCL one phosphorylation is regulated
• 24:32by both MAP kinase and also there's a
• 24:36stead pathway dependent phosphorylation.
• 24:38So when MCL one is phosphorylated it's
• 24:41stable so the levels are increased
• 24:43and the product cannot be degraded
• 24:45otherwise it's short lived protein.
• 24:47So essentially there's also some
• 24:48B cell XL component,
• 24:49but I think it's a minor,
• 24:51but the nice thing is all downstream
• 24:52or Flix 3 ITD.
• 24:53So it's OK if we're here Flix 3
• 24:55what happens with MCL one.
• 24:57So we used Quizactinib for that matter and
• 24:59we showed nice inhibition of the Flix 3 MCL.
• 25:02One did go down by wasn't that
• 25:04huge up down regulation.
• 25:06But we also show that the protein
• 25:08called BEM was induced and BEM
• 25:10can is a prop of Tory BC on a
• 25:13protein that can inhibit MCL one.
• 25:15So the combination of these two
• 25:18makes cells sensitive to venetoclax.
• 25:21And this is BHA profiling essay
• 25:23which I have time to explain in
• 25:25detail by essentially you throw
• 25:27the peptides on the cells and see
• 25:30which dependence that they have.
• 25:32But the point here is that if you
• 25:33treat cells with Flix 3 inhibitors,
• 25:35you have huge up regulation of B.
• 25:37So two dependency to the peptide
• 25:39or to the actual venetoclax drugs.
• 25:42So you have synergy in vitro.
• 25:44And in this model,
• 25:45which there was like a subcutaneous model,
• 25:47not a great model for AML,
• 25:49but we subsequently publish also PDX models,
• 25:51we show like essential cures
• 25:53of the mice for that matter,
• 25:55when we use the Quizad,
• 25:56snip and Venetoclax combination.
• 26:00So this did go into clinical development.
• 26:02And for the trials another flixster
• 26:05inhibitor second generation
• 26:07guilt treatment was selected.
• 26:09And this paper is now published in
• 26:12JCO by MD Anderson Group and many
• 26:15other collaborators where there was
• 26:17combination of venetoclax and guilt
• 26:19retina for relapse refractory Flex
• 26:213 mutated AML.
• 26:22And there was quite significant response
• 26:25rate in all patients or in those
• 26:28who failed prior Flex 3 Tki's alone.
• 26:31And if they went for the transplant,
• 26:33they actually the survival looks fairly good.
• 26:37The data by Kathy Smith showed
• 26:39that the Flixtree clones were
• 26:41extinguished after this combination.
• 26:42I have to say that she did show
• 26:44that Ras clones were coming
• 26:46up in patients who progressed.
• 26:47So Ras is still a resistance
• 26:49mechanism even in that setting.
• 26:52But again,
• 26:54this was quite impressive sort of
• 26:57advance in the field of Flixtree mutated AML.
• 27:00Now of course we all know that treating
• 27:03patients is best at the time of diagnosis.
• 27:05So for all the patients we
• 27:07cannot use chemotherapy.
• 27:08So Ambiencin's group has
• 27:10pioneered what we call triplet.
• 27:12So triplet is essentially Azovan
• 27:14which is a backbone and then you
• 27:16add the third drug in this case
• 27:18is guilt written and this paper
• 27:20is also now accepted in JC or now
• 27:22this is single sounded trial.
• 27:24There's a lot of discussion on Twitter
• 27:26whether it's like you know true or not,
• 27:29but at least you know data from
• 27:31Indiannis and look very impressive.
• 27:34Now when you see 100% response rate,
• 27:36you always kind of pause,
• 27:37but that's what they reported and 30
• 27:40newly diagnosed patients with AML and
• 27:43they estimated survival at two years was 70%.
• 27:46So this is like way better
• 27:48than what we had before,
• 27:50but they had to like reduce a
• 27:52lot of duration of the drugs and
• 27:54work out the schedule because the
• 27:56combination is mild suppressive.
• 27:57So the major like heme toxicity of
• 27:59venetoclax is mild suppression.
• 28:01So Neutropenias because Mallo
• 28:03itself express B so too.
• 28:06And so when you use the vanadium
• 28:08clocks in combinations,
• 28:08you have to cut back and that's
• 28:11continued discussions with FDA
• 28:12because the approved scale is 28
• 28:15days of vanadium clock.
• 28:17So there's a randomized study right
• 28:18now ongoing which hopefully will
• 28:20kind of solidify this question run
• 28:22by a Stellas and AbbVie where the
• 28:25same combination is being used in
• 28:27the frontline all the AML settings.
• 28:29So we'll see how that goes,
• 28:32but again what do we do about Ras.
• 28:34So this is like very early preclinical work.
• 28:38We're working with Everest Gavasitis at
• 28:41Einstein and he developed the RAF inhibitor.
• 28:44So kind of downstream of Ras that inhibit
• 28:47is allosteric RAF inhibitor that he
• 28:50is about to publish in solid tumors.
• 28:53But we show that P in cell lines
• 28:55with K or N Ras mutation is highly
• 28:58effective drug using inhibition
• 29:00of the pathway and there's some
• 29:02additive effects with venetoclax.
• 29:04So we kind of continue working on that.
• 29:06So hopefully we'll get either
• 29:08Ras inhibitors or RAF inhibitors.
• 29:09We did test the MECH inhibitors.
• 29:12I didn't show you that we published that.
• 29:14We went all the way into clinic,
• 29:15but MECH inhibitors caused a lot of
• 29:18GI talks and so the trial was unsuccessful.
• 29:21So it was stopped for lack of
• 29:24efficacy and high
• 29:25toxicity. So we can't really use the Mac
• 29:28inhibits unfortunately in this combination.
• 29:30So work to be continued on this topic.
• 29:34So there are a lot of other
• 29:36combinations with banana glass
• 29:37that have been sort of published.
• 29:38This is just some nice summary that
• 29:41was presented at last EHA and the
• 29:44the combination with IDH inhibitors
• 29:46that are now in clinical trials and
• 29:49both in AML and MDSI have to say
• 29:52there's many inhibited combination
• 29:54which looks super exciting.
• 29:55Of course, I'm still 1 went to to trials,
• 29:58but it's struggling.
• 29:59There was McGraw mop combination
• 30:02which we pioneered,
• 30:03but right now McGraw mop is
• 30:05all the trials have stopped.
• 30:06So I'm not going to talk to you about
• 30:09that today and but I want to show some
• 30:11data with the immune approaches in
• 30:13this case is antibody drug conugate.
• 30:15So kind of a little bit different
• 30:17story with venetoclax.
• 30:18So, so we used the,
• 30:21we looked at CD 123 because CD 123 is
• 30:24a subunit of all three receptor alpha
• 30:27and it's ubiquitously expressed in AML.
• 30:30Also this other level of my
• 30:32BPDCN and in some ALR as well,
• 30:35it's expressed in stem cells based
• 30:38on Craig Jordan's work and it's
• 30:40sort of the only antigen right now
• 30:42that we kind of trying to target as
• 30:44far as immune therapy and EMLMDS.
• 30:46There are other efforts but none
• 30:48of them have been successful yet.
• 30:51So we've been working with this
• 30:53company Immunogen that developed
• 30:55the antibody drug Conugate.
• 30:57So they have the antibody gain C123
• 31:01that's through the linker is bound
• 31:04to the alculator that produces
• 31:06the single strand DNA damage.
• 31:09So obviously it's internalized and
• 31:12and you know kills the cells for
• 31:14the DNA damage kind of chemotherapy
• 31:17but in a targeted fashion.
• 31:19So it had the good single agent
• 31:22activity and BPDC and then EMO
• 31:25the company has filed approval for
• 31:27BPDC and patients a second line.
• 31:29So hopefully we get this drug
• 31:31approved pretty soon.
• 31:32And so we of course asked the question,
• 31:34can we combine the two because
• 31:36this is like you know the immune
• 31:37therapy that seems to be working.
• 31:39So we've done quite a bit
• 31:40of preclinical work.
• 31:41It's not published yet,
• 31:42but we show that the compound is fairly
• 31:45specific. So these are AML cells.
• 31:47This in red is CD123 expression.
• 31:50So again,
• 31:50majority of cells do express it and
• 31:53they're being killed by this drug,
• 31:55but then the cells that don't express
• 31:58there's no killing and KG one is resistant.
• 32:00We're not quite sure why,
• 32:02but it seems to be specific.
• 32:04And then we ran the combinations
• 32:06both with another clogs and
• 32:08azacitidine and the triplet because
• 32:09now we're in the triplet era, right?
• 32:12And you can see here.
• 32:13So these are different cell lines.
• 32:15I have to say that ITD cells
• 32:17have high expression of C123,
• 32:18which is why we selected those
• 32:20for the combination trials.
• 32:21But especially with the triplet,
• 32:23there's quite a bit of synergy.
• 32:27What about PPG mutant AML,
• 32:30So these are wild type cells,
• 32:31so they're sensitive and they mutant or loss,
• 32:35PPG loss, we see less activity.
• 32:38There's still some induction of cell does,
• 32:40but it's actually quite resistant
• 32:42to both of the compounds.
• 32:44We're not quite sure how that is affected.
• 32:46So for some reason the cells
• 32:48had very high expression of MSL.
• 32:49One, we're still working on to understand
• 32:52that because we did see induction of
• 32:54DNA damage in both knock down cells
• 32:56and the wild cap cells and there's a
• 32:59part cleavage but it's less killing and
• 33:02that is also reflected in the trial.
• 33:04The PhD media patients didn't
• 33:06do as well as you can imagine.
• 33:09The drug abolishes the S phase.
• 33:11So this is like IMGN alone and the
• 33:15different concentrations and then
• 33:16when you combine with the Vanasa you
• 33:19essentially you kill off the S phase
• 33:21cells so you don't have anything left.
• 33:24You do get activation of gamma H3X
• 33:26as adna damage and Cliff cast space.
• 33:29So then we try to understand the mechanism,
• 33:31how that works.
• 33:34And so one thing is we know that
• 33:36again I'm Gen.
• 33:37inducing the single cell DNA strand breaks.
• 33:40So we showed the phosphor P53UP
• 33:43regulation which was the same
• 33:45with or without venetoclax.
• 33:47But then we saw that the drug inducing
• 33:50the DNA repair pathway phosphor check one
• 33:53and it seemed to be less with venetoclax.
• 33:56So we are,
• 33:57it's kind of off story,
• 33:58but we are trying to understand if
• 34:00BCL 2 inhibition can actually be
• 34:02involved in the control of DNA damage,
• 34:04which is hard to understand because
• 34:06it's cytosolic and this is DNA.
• 34:08But we are kind of working through the story,
• 34:11still trying to figure out all
• 34:12the parts of the DNA pathway.
• 34:15But it has some like clinical,
• 34:16preclinical implications because if you
• 34:18use IMGN first followed by the nether class,
• 34:22you have very striking synergy.
• 34:24This BLISS index is 18.
• 34:26If you do the reverse then
• 34:28first followed by IMGN,
• 34:30there's very little synergy now in
• 34:32the clinic it's given concomitantly.
• 34:35So I think it's fine but and nobody's
• 34:38interested in understanding the kinetics.
• 34:40But I think the biologically this
• 34:42is interesting phenomenon and
• 34:43perhaps something to do with DNA
• 34:45damage repair that we're working on.
• 34:47We also showed that the IMGN primes
• 34:50towards be so to inhibition.
• 34:52So I didn't I have a lot of like
• 34:54mouse data which I didn't show you,
• 34:56but the clinical trial has been
• 34:58reported at ASH and the paper is
• 35:01also now accepted in JCO.
• 35:03So this is a triplet.
• 35:05So again the drug is now called
• 35:08Pivacomab P VAC.
• 35:09We abbreviate that it was used with
• 35:12Azovan in newly diagnosed AML.
• 35:14All the patients,
• 35:15you know majority were unfit,
• 35:18but there were some fit patients as well.
• 35:21So it was fairly safe.
• 35:23So again the drug has some toxicities,
• 35:26but generally speaking it was well tolerated.
• 35:30And then the response rates where I
• 35:32would say similar to the ACE event,
• 35:34but what was impressive
• 35:36was MRD negativity rate.
• 35:38So the depths of response was you get about
• 35:4240% with ACE event it was about 76% of 79.
• 35:45So almost doubling the depths of response.
• 35:48Now we don't know yet if that
• 35:50translates into survival,
• 35:50which will be a critical question.
• 35:53So now Immunogen is bought by ABB vie.
• 35:55So we're hoping that this will continue
• 35:57and to randomized phase three study
• 35:59and maybe we'll have that triplet in
• 36:01a few years fully characterized that.
• 36:04But if you look at this like 3 subsets
• 36:07that I showed you before, so again,
• 36:09the good kind of prognostic patient
• 36:11that respond well to to azavan,
• 36:13they did really well.
• 36:15This response rates in PVC mutant,
• 36:18there was about 20% full CR rate,
• 36:21but 50% overall response rate.
• 36:23So maybe there's kind of,
• 36:25you know some signal again with PVC mutation,
• 36:28we are kind of really at loss.
• 36:29So that you know,
• 36:31but again this will be developed
• 36:33hopefully further and we'll see a few
• 36:36years from now where that lens now P 53.
• 36:39So I already told you several times that this
• 36:42is like a major unmet need in AML and MD's.
• 36:45All the drugs that we had in phase
• 36:47three have failed for the most part.
• 36:49And even from the very initial studies,
• 36:52we've showed that this was a major resistance
• 36:55factor to venetoclax as well unfortunately.
• 36:57So patients who again relapsed
• 36:59or who were primary fracture,
• 37:01they had high rates of 17 P loss or P50C
• 37:07mutation or both and why that is the case.
• 37:11So first of all if you do like
• 37:13single cell DNA sequencing,
• 37:15this is from Andrew Way's paper
• 37:17you showed you know all this
• 37:19clones are being selected for.
• 37:21So it's almost like a pressure to select
• 37:23this clones for that because they do
• 37:25not get killed by venetoclax cell.
• 37:27And what he showed in this paper is
• 37:30that while in parental cells venetoclax
• 37:33induces backs activation by this essay,
• 37:36there's much less in the PVC knockouts also.
• 37:39And you can sensitize it by MC1 inhibition.
• 37:43But again,
• 37:44we don't have MC1 inhibitors in the clinic.
• 37:46So what do we do about that?
• 37:48We we don't really know.
• 37:49But I want to show you some clinical
• 37:51data from our Einstein program that
• 37:53was developed before I got there
• 37:56using a different approach.
• 37:57So the approach that they decided to go
• 38:01forward was really developed by Jogan.
• 38:04I cannot promise the last name,
• 38:05but that at Cleveland Clinic.
• 38:08So he is I think,
• 38:08the most knowledgeable person
• 38:10in HMAI feel that.
• 38:12So essentially he published
• 38:14the first study in MD's,
• 38:15as I'm sure Amara knows very well.
• 38:17And he compared the traditional dosing of
• 38:20decybin with what he calls metronomic dosing,
• 38:23which is once a week like 1/5 of the dose.
• 38:25So really like tiny doses of decybin.
• 38:28But he showed that this is
• 38:31enough to deplete DN MT3DMT1.
• 38:32So you don't really need to induce this,
• 38:35you know, constant cytotoxic
• 38:37DNA damaging response of HMAS.
• 38:40And then he showed in preclinical work
• 38:42that it can induce differentiation
• 38:44of P53 novel loss clones.
• 38:46Now the resistance to the decided
• 38:49men is mediated by approvalation
• 38:52of pyramid and synthesis.
• 38:54Again, this is all his work and
• 38:57he had some preclinical data
• 38:59that Veneto clerks can in fact
• 39:02reduce the pyramid incentives.
• 39:04So there may be potential synergy there.
• 39:07So based on this sort of
• 39:10preclinical rationale,
• 39:11the team at Einstein have
• 39:14developed this metronomic dosing
• 39:16of Decidabin and Veneto clerks.
• 39:18So now you have a newly diagnosed
• 39:20patient with Amalo MTS who comes
• 39:22to clinic and gets once a week
• 39:24injection of the SIBIN subcutaneously
• 39:26and one dose of another class.
• 39:28So I'll say I had hard time
• 39:30believing that when I got there,
• 39:32but I think now I'm so converted and
• 39:34that we are continuing the development
• 39:37of this in the prospective trial.
• 39:40So again this is like a schedule,
• 39:42this is like traditional what you do,
• 39:44you give another class for 28 days
• 39:45and you give the SIBIN for five days
• 39:48or ASAP for seven days and then you
• 39:50repeat the cycle and he is like once a week.
• 39:53So the idea is really to get away from
• 39:55the DNA damaging response because we
• 39:57know that Pfc mutated cells are only
• 39:59being selected by any DNA damaging drugs,
• 40:02they don't care and get into
• 40:04this hyper misleading effect.
• 40:06How that works, we don't know right?
• 40:08How many agents mechanism of actions
• 40:10is still not fully understood,
• 40:13but the idea was can we like really use
• 40:15that approach and at least have some benefit?
• 40:19So they published this paper,
• 40:20this was retrospective study using
• 40:22this regimen and now as I said,
• 40:24we are in the prospective study.
• 40:26I'm sorry,
• 40:26it's a it's a bit difficult slide
• 40:28but the point is that there was
• 40:31no really like mouse suppression
• 40:33but the response rate was quite
• 40:36significant and CR rate was 57% which
• 40:39was fairly similar to the VLA study.
• 40:42And then when we looked at the small
• 40:44numbers again this is all like very
• 40:46early on of PVC mutated patients,
• 40:47the survival was about 10 months
• 40:49and a lot of patients actually
• 40:51achieved full remission,
• 40:52became transfusion independent
• 40:54and they did very well.
• 40:56They relapsed like a clock at 10-11 months.
• 40:59So it's not curative approach but
• 41:00at least you know we can extend the
• 41:03survival again and reality is five
• 41:05months survival. Many other studies.
• 41:06Now this is 10 months.
• 41:08Again, small number non randomized studies,
• 41:10so with all the Kevas,
• 41:12but we're quite excited about
• 41:14that and we are thinking of what
• 41:15can we add to that to really like
• 41:17capitalize on this approach,
• 41:19you know using this metronomic dosing.
• 41:23So one thing is like in the lab we are
• 41:25trying to use some of the BAX activated.
• 41:28So I told you several times the
• 41:30BAX is really like critical and
• 41:31the BAX is not working with PP,
• 41:33she's lost. So we have a collaboration
• 41:37with again Everest and also Jerry
• 41:40Chipok would develop the direct
• 41:43Bax activators or Bax modulators.
• 41:46So we are thinking maybe
• 41:47if we use those compounds,
• 41:49there's a preclinical stage we
• 41:51can overcome the PVC mutant loss,
• 41:53but this remains to be seen.
• 41:56OK. So switching gears,
• 41:58so this was PVC new dated AML and
• 42:00now going back to the chemotherapy.
• 42:02So as I showed you before,
• 42:04there's like very good rationale to
• 42:06combine the Netherlands with the
• 42:07chemotherapy and AML and there are
• 42:09a lot of trials which have been
• 42:11already reported and now we're getting
• 42:13the response rate of about 90%.
• 42:15So this is like like was unheard of before,
• 42:19but when you add the Netherlands
• 42:21to chemotherapy you really get
• 42:23tremendous synergy.
• 42:24So in our centre we have this
• 42:26also IST that is run by Doctor
• 42:28Manzaris where we use the standard
• 42:30Sam plus sheep plus another class,
• 42:32different durations and so forth.
• 42:35The trial is still ongoing,
• 42:36but again the response rate are about
• 42:3890% is still like short follow up.
• 42:40So we don't really know like survival,
• 42:43but we are quite excited about this
• 42:45approach except PVC MUDA patients,
• 42:47they relapse and they don't do well.
• 42:49So we stopped using this for even
• 42:51younger PVC MUDA patients because all
• 42:54patients, 5 patients were treated with,
• 42:56they're all relapsed and they died
• 42:58from despite the fact that some
• 43:00of them achieved remission.
• 43:02So again, PVC remains an issue.
• 43:04So we're looking at the stem cell
• 43:07extinction with the therapy and
• 43:08doing a lot of research with that.
• 43:11And in the last 10 minutes of my talk,
• 43:13I'll go back to BCL XL,
• 43:14which may be of interest more
• 43:17broader kind of auditorium.
• 43:19So BCL XL is a cousin of BCL two
• 43:23and it's less expressed in the AML,
• 43:25but it's expressed in solar tumors,
• 43:28it is expressed in the TELL subsets.
• 43:30So this was work from Tony Lataev
• 43:33now a few years ago,
• 43:34a number of years ago that showed
• 43:37that the typical TELL actually
• 43:39depends on BCL XL and if you use this
• 43:42Navitoclax drug that didn't make it,
• 43:44you actually get very good responses.
• 43:46There's a subset that is B,
• 43:48so two dependent,
• 43:48but I'm not going to go into that.
• 43:51Now.
• 43:51I already told you that the
• 43:53liability of B cell X inhibitors is
• 43:56thrombocytopenia because platelets
• 43:57depend on B cell XL for survival.
• 44:00So you get on target toxicity and of
• 44:03course it's challenging to those.
• 44:06So and you know this is just a
• 44:08couture published review recently.
• 44:10So Nevito clocks right the drug
• 44:12that is still not approved,
• 44:13it was just as the venetoclax so
• 44:16inhibits the complexes inducing bags
• 44:18back but it causes thrombocytopenia
• 44:21killing the platelets.
• 44:22So the way around that at least
• 44:25that's ongoing work is to use the
• 44:28degraders for BCLXL degraders.
• 44:30So,
• 44:31so we have been collaborating with
• 44:34the team from Dalhoung Zhou who
• 44:36was before University of Florida
• 44:38and now he
• 44:39moved to the San Antonio.
• 44:40So he developed this Protac BCL
• 44:44XL degrader where the legend
• 44:47is essentially native o'clock.
• 44:48So same drug, but then there's a linker
• 44:52that links it to the VHL E3 ligase.
• 44:54So you can ask why that is
• 44:56better than inhibitor, right?
• 44:58First of all, it's huge molecules.
• 44:59So it's has a pharmacological
• 45:01properties issues.
• 45:02But The thing is that this E3 ligase
• 45:05is not expressed in platelets.
• 45:07So you're not getting degradation
• 45:09of B cell XL and platelets.
• 45:11And therefore you can see here
• 45:13there's no B cell cell degradation
• 45:15in platelets with this drug.
• 45:17But it's like a TLO tumor cell line,
• 45:20it's very nice degradation.
• 45:21So this is just the schematics of that.
• 45:24And again as a result,
• 45:26you can kill the tumor cells
• 45:29but you don't kill platelets.
• 45:31So this drug right now is in clinical
• 45:34trial in solar tumors and it's actually
• 45:37completed the phase one portion of it.
• 45:40They did see some drop in platelets,
• 45:42but there was much less than whenever
• 45:44the clocks I think because the drug
• 45:46still binds to some extent and still
• 45:49inhibits a little bit of BCL XL function,
• 45:51but it was reversible and
• 45:53no other toxicity was seen.
• 45:55We published that it's quite effective
• 45:57and the TL models and recently we
• 46:00also moved towards the dual BCL 2XL
• 46:04product which is not yet in the clinic
• 46:06and we published this work in AML
• 46:10and we showed that this dual product,
• 46:11we call it 753-B,
• 46:13it was actually quite effective in all
• 46:15primary AML samples including those
• 46:17that were resistant to venado clock.
• 46:20So there's you know there's
• 46:23degradation of BCL XL as you would
• 46:25expect basically didn't see much
• 46:27degradation of BCL 2IN primary cells
• 46:29but it was seen the cell lines.
• 46:31So we think that's potential for using
• 46:34dual BCL 2XL inhibitors in AML as well.
• 46:38And the other aspect of it that is
• 46:40very kind of popular and the solid
• 46:42tumor literature is that the role of
• 46:45B cell excel in senescence cells.
• 46:47So what we know the senescence cells,
• 46:49the cells that survive chemotherapy
• 46:51and but they can kind of revert back
• 46:55and become chemo resistant and the
• 46:57metastatic cells in the setting of
• 47:00breast cancer or lung cancer and so forth,
• 47:03It's much less known in senescence in EMO.
• 47:06But there was a paper by Ari Melnick's
• 47:08group that showed that chemotherapy
• 47:11can actually induce senescence cells.
• 47:13So this is like essay you use for
• 47:15the C-12 FDG where you can show that
• 47:18within the viable cells a fraction
• 47:21of them are actually senescence and
• 47:24the senescence cells they depend
• 47:25on BCL X cell for survival.
• 47:27So when we sorted out the senescence cells,
• 47:29we showed that BCL XL was up regulated
• 47:31which was which was consistent
• 47:33with the literature.
• 47:34And then when we looked at the markers
• 47:36of senescence, this is cell line.
• 47:38So chemo is inducing all the
• 47:39senescence phenotypes.
• 47:41But when we use this BCL XL
• 47:43degrade that we
• 47:44can reverse that and
• 47:45they showed here as well.
• 47:47So we think that there's a potential
• 47:49efficacy of BCL XL inhibition and this
• 47:52dormant senescence cells plus with
• 47:54it's really hard to like identify them
• 47:57and patients like you know the the
• 47:59essays are not very well established.
• 48:02But I think there's a lot of interest
• 48:04using BCXL inhibitors as synolytic
• 48:05in a variety of different sort of
• 48:08conditions including sorry tumors,
• 48:10leukemias and so forth.
• 48:11And the finally,
• 48:13like I told you that there's some
• 48:15AML subsets that are BCL Excel
• 48:17dependent and this is one of them.
• 48:19So this is like totally horrible
• 48:21entity called acute Erythroid,
• 48:22Erythroid leukemia.
• 48:23And now Doctor Xu here has done
• 48:26a lot of work on that,
• 48:28but it's in the old classification
• 48:30is the MLM 6 and it has all of this
• 48:34Erythroid markers and it has very
• 48:36high rates of PPC mutation, right.
• 48:38So I already told you that the NOW
• 48:40class does not work for PPC mutant AML.
• 48:42And sure enough in all clinical
• 48:44trials patients who were AEL patients
• 48:46who were treated with Venetoclax,
• 48:47they progressed very quickly.
• 48:49So that's not a solution,
• 48:51but there was a,
• 48:54we collaborated with the work with
• 48:55a group at University of Helsinki
• 48:57and they they published this very
• 48:59nice paper last year and blood.
• 49:01So they looked at the dependency
• 49:03and AEL using the Crispus screens
• 49:06or drug screens and one of the
• 49:09top one was actually B cell XL.
• 49:10This is a gene called B cell
• 49:1312/1 that controls B cell XL.
• 49:15And you can see that it also was
• 49:17true for the drug screen as well.
• 49:19They show this and they confirm that
• 49:22and the cell lines and if you use a
• 49:25different like gene expression data sets,
• 49:26so again this is old M6 also
• 49:28M7 which is megacaric leukemia,
• 49:31they have high expression here,
• 49:33very high expression and this
• 49:34is Saint Jude Court as well.
• 49:36So they have a high expression of
• 49:38BCL XL on a transcriptional level.
• 49:41So The thing is because the
• 49:43erythroid cells have you know
• 49:44naturally utilizing this protein
• 49:45for survival and this is preserved,
• 49:48they also showed some efficacy
• 49:50in the in vivo models.
• 49:51So we are interested in using the
• 49:53product for this indication and
• 49:55within mechanistically it makes a lot
• 49:57of sense because again in Aristo it
• 50:00says the main transcription factor
• 50:02that drives kind of development
• 50:04is gutter one and we show that
• 50:07there is a very direct correlation
• 50:08between B SO2L1 and gutter one.
• 50:11This is activity from the gene expression
• 50:13analysis and both different data sets.
• 50:16This was collaboration with Saint Jude team,
• 50:18so there's no correlation with BCO 2.
• 50:20So really in Ali think there's
• 50:23transcriptional up regulation
• 50:25and dependency on BCL XL.
• 50:27Based on some of the prior work published,
• 50:30we know that this got the one
• 50:32directly binds the BCO 2L1 locals.
• 50:34And we have now also data in
• 50:37AL in collaboration with again
• 50:39Ilaria from Saint Jude
• 50:41and they're using this degrader.
• 50:44So this is original BCL XL degrader.
• 50:46This is like a next generation.
• 50:48We showed us the cell lines that are
• 50:51completely resistant to the netoclocks
• 50:52here and green they can be nicely
• 50:55killed by this B cell cell degrader.
• 50:58We also tested this in fuel primary
• 51:00samples that you know failed all kind
• 51:03of regiments including macrolimab and
• 51:05the we show the B cell degradation
• 51:08here and very nice response.
• 51:10So again, this is preclinical work.
• 51:12We're trying to get the drug if we get
• 51:15funding for the trials is still ongoing,
• 51:18but we feel that this is a hopeful
• 51:21and in fact I learned that every
• 51:24just approved the nabito clocks
• 51:27for the subset of AL between MSK
• 51:30and the MD Anderson Cancer Center.
• 51:33So there will be a small pilot
• 51:34trial at least testing the proof
• 51:36of principle that B cell XL is a
• 51:39driver in this horrible disease.
• 51:40We also see very similar phenotypes in MPN,
• 51:43but I didn't have time to
• 51:45show this data as well.
• 51:47So I'll end here.
• 51:48And I would like to postulate
• 51:50that AML is generally B,
• 51:52so two dependent disease,
• 51:53but then there's some subsets that are
• 51:56depend on B cell XL or M cell one.
• 51:58And of course we love the drug because
• 52:00it kind of lowers the threshold.
• 52:02So you can see the synergy with pretty
• 52:05much anything you use and then you can
• 52:08kind of go back to lab and figure out why.
• 52:11But but this was really like you know
• 52:13born in the clinical trials where I
• 52:16showed you synergy with chemotherapy,
• 52:18with the hypermethylene agents,
• 52:20with thyristine kinase inhibitors and
• 52:22you know the the fuel has really like
• 52:25exploded using this drug as a sensitizer.
• 52:28Some of the you know trials that I
• 52:31mentioned are ongoing and immune
• 52:33therapies I mentioned to you before
• 52:35now resistance is obviously as a major
• 52:38issue and it's largely driven we think
• 52:41by PC laws or signaling mutations.
• 52:44And you know I showed you what
• 52:46we're trying to do about that.
• 52:47But then the subsets that are B cell
• 52:50excel dependent and we are quite
• 52:52excited about using this B cell excel
• 52:55inhibitors or products in this setting.
• 52:57So I'll end here.
• 52:58So I have many,
• 52:59many Co workers collaborators from
• 53:02both my MD Anderson lab that has now
• 53:07only partially moved to Einstein.
• 53:08So I have a new lab at Einstein and
• 53:11my clinical collaborators at MD
• 53:13Anderson especially Courtney who led
• 53:15AMLVLA trial now who has done a lot
• 53:17of triplet combinations and many
• 53:20other investigators of course Dr.
• 53:22Contagion who has been really like
• 53:24pushing ABVI to go forward with this
• 53:27HMA event trial despite the fact that
• 53:30single agent was not as efficacious.
• 53:32And a lot of collaborators from
• 53:35Montefiore Einstein,
• 53:36we're developing this new programs
• 53:37that I showed to you and many
• 53:40collaborations with the companies
• 53:41but also academic collaborators.
• 53:43So I would like to acknowledge
• 53:45Tony Li Tai
• 53:45who has been really like,
• 53:47you know, developed this first
• 53:49approach with me in the lab.
• 53:52And you know, we think that because of
• 53:54that work and algos really went into AML
• 53:57and we have collaboration with Andrew
• 53:59Way at Melbourne and with the Saint
• 54:01Jude team and Dao Hangzhou for the product.
• 54:04So I'll end here.
• 54:05Sorry, it's like 5 minutes before
• 54:06the end of the hour,
• 54:08but I am happy to take questions.
• 54:10Thank you. Maybe I
• 54:19can start.
• 54:22You have questions in Zoom
• 54:26a fantastic talk.
• 54:28Very few people actually bridge
• 54:30the the clinic and the lab like
• 54:32you do clinical trials and lab,
• 54:34which is amazing.
• 54:35So I know this is not
• 54:37primarily your research,
• 54:38but why would you think the metronomic
• 54:40use of HMA with venetoclax would
• 54:44actually work for TP50 TP 53
• 54:47while regular dosing would not?
• 54:50I think the regular dosing induces
• 54:52DNA damage and essentially leads
• 54:54to the selection of P53 lost cells,
• 54:57so you kind of lose your hypermethylene
• 55:00advantage, whatever that is.
• 55:02Again, I don't know how the hypermetalline
• 55:05agents work in PhD muted EMLO,
• 55:07but I think what happens with the
• 55:09regular dosing, there's DNA damage,
• 55:11which was shown by Steele,
• 55:12Gore and others before.
• 55:14And the cells,
• 55:15they're just like being selected for.
• 55:17So all you get is selection of
• 55:19cells that are like PHC mutated.
• 55:21They're resistant to DNA damaging drugs.
• 55:23And so there's very limited like advantage.
• 55:26Well, with metronomic dosing you
• 55:28really like rely on hypometallic
• 55:30effects of the drug and then
• 55:32you know you you get benefit.
• 55:34But again you know it's
• 55:36a hand waving argument,
• 55:37but we are encouraged to see that
• 55:40in the prospective trial with
• 55:42the you know about 10 patients
• 55:44treated that the data stand.
• 55:45So this you know again they're going
• 55:47to remission about like 5060% and as of
• 55:50right now survival is about 11 months.
• 55:52But again like short follow up,
• 55:54you know it's a small number of patients.
• 55:56So I'm like you know,
• 55:58I've been hesitant presenting
• 55:59this data till I actually,
• 56:00you know, saw the survival data,
• 56:03but we're hoping that you know this
• 56:05will stand, but again it's not curative.
• 56:07So we definitely need something
• 56:08else to add to that.
• 56:10Thank you,
• 56:17very nice talk. I was curious
• 56:19about what's being done towards
• 56:22tissue specific MCL ONE inhibitors.
• 56:25So in order to avoid the cardiotoxicity,
• 56:28you talk beautifully about BCL
• 56:29XL for example. Unfortunately,
• 56:32nothing that I'm aware of.
• 56:35I heard that there's some approaching
• 56:38making approaches making the ADC.
• 56:42I haven't had yet chance to
• 56:44get any of those to my lab.
• 56:46So people are thinking about that.
• 56:49I think it's probably ongoing,
• 56:51but I'm not aware yet that
• 56:52there's any like you know,
• 56:53compound that is close to clinic,
• 56:55but I think that would be the way to go.
• 56:58Now the VHL is expressing the heart.
• 57:02So you know,
• 57:03there's also effort by Stephen Fazek,
• 57:06who is now at the Vanderbilt to look
• 57:09at all 600 ubiquitin ligase and try
• 57:11to understand the tissue specificity.
• 57:14Obviously, if I'm so one,
• 57:15we have to avoid the heart.
• 57:17I think that effort is still
• 57:18ongoing as far as the products,
• 57:20but I think perhaps using the antibodrap
• 57:25conugate maybe is the way to go.
• 57:27You know there was the B7 HCB cell Excel
• 57:31conjugate that went into solid tumor trials.
• 57:34It somehow didn't make it,
• 57:35but kind of similar approach
• 57:36perhaps can be used in Amo,
• 57:38but nothing close to clinic yet.
• 57:41Thank you.
• 57:44Thank you for that. Thank you.
• 57:48Looking at the evolution on the
• 57:49clinical slides that we show on track
• 57:51right single agent one of the plaques,
• 57:53we are very modest activity in AML
• 57:56That phase three study that you show
• 57:58with Curtney in the first three months
• 58:00ASA one curves don't separate after
• 58:03that the curves start to separate but
• 58:06everybody needs a CR after one cycle.
• 58:09I think what are we doing there
• 58:12I think the probably the people don't
• 58:14die with ASA after first month either.
• 58:17So they still you know this well with
• 58:19ASA side is about nine months right.
• 58:21So they even though they don't get
• 58:24intermission, they are still, you know,
• 58:26alive and they continue on study
• 58:28and so they curve separate later.
• 58:31That's my guess. But you're right.
• 58:33You know, remissions happen after one to
• 58:35two months with the vanilla clocks and
• 58:37there are no remission with azacitidine.
• 58:40But it's because I guess they're still
• 58:43kind of able to maintain people alive with
• 58:45all our supportive care and everything.
• 58:47They they are still there.
• 58:50That's my understanding
• 58:52because you know if you go back into
• 58:53that paper that you're a part of the
• 58:55Curtis paper that frankly presented
• 58:57at the older NPM on positive.
• 58:59I have a feeling when Nick presents
• 59:01the data after that combination,
• 59:02they're highly choosing NPM on positive
• 59:05patients that is chemosensitive
• 59:07or mild suppression sensitive.
• 59:09And then they're tagging it up with
• 59:11the fixed data because they're seeing
• 59:13a flat like that kurtish paper
• 59:15you have the first three months,
• 59:16it's a flat drop, drop,
• 59:18drop and we know what addition of three
• 59:21class of frequently liberals done too.
• 59:23And
• 59:25the point being is AML being all legal
• 59:28flow now, how much emphasis can we
• 59:31give just the BCL component in looking
• 59:33into resistance because the minor
• 59:35suppression component takes care of it
• 59:37for three to six months, very good.
• 59:39We don't have anything to that extent
• 59:41compared to cytotoxic in the past.
• 59:44Garcia within a recently in the post
• 59:46transplant period in the other one has
• 59:48maintenance even there the curves first
• 59:50three to six months and then drop,
• 59:51drop, drop, you don't have a
• 59:53leukemia there at that stage.
• 59:55So now when I'm going to fight stem cells,
• 59:57what do you think the resistance is in
• 59:59that context when you're using either
• 01:00:00one in the post transplant context?
• 01:00:03Oh I I don't think I'm able
• 01:00:04to answer that question. So
• 01:00:09I'm not sure what the you know.
• 01:00:12I don't think that this is just mouse
• 01:00:14suppression causing people to die,
• 01:00:15but there's really like relapses going on,
• 01:00:18right? And I assume that this is
• 01:00:20still escape of some of the clones
• 01:00:22that are not being eliminated.
• 01:00:24But I don't know the data that well.
• 01:00:27But yeah, the point is well taken
• 01:00:28that you know the triplet, the data.
• 01:00:32As far as like you know,
• 01:00:33there's a lot of discussion
• 01:00:34if you have MP1 free, St.
• 01:00:36Commutative clone can be eliminated
• 01:00:38with Venetoclax alone or not.
• 01:00:40The data are not very clear,
• 01:00:42but at least from VLA data
• 01:00:44we know that Flixtree mutated
• 01:00:45patients even if they had MPN one.
• 01:00:48This is not published,
• 01:00:49but I looked at that in the rest context.
• 01:00:52The survival is still shorter than
• 01:00:54for those who have only MPN 1.
• 01:00:56So there's still that contribution
• 01:00:58of the Flixtree clone to the
• 01:01:00like relapse earlier Relapse,
• 01:01:01despite the fact that you target the,
• 01:01:03you know, presumably stem cell MPN,
• 01:01:05one clone with Venetoclax.
• 01:01:07But I don't know really how like
• 01:01:09Clonal Dynamics happened there,
• 01:01:11but I do think that triplet adds in
• 01:01:13that sense that it will target the
• 01:01:16fixture clone within even MP one.
• 01:01:18But again, you know,
• 01:01:19I don't have data to that.
• 01:01:22So maybe one last question,
• 01:01:24given your extensive work with drug
• 01:01:27development in AML and you alluded to
• 01:01:29the Twitter wars on some of these data.
• 01:01:32I think one big question that
• 01:01:34keeps coming up is if if an agent
• 01:01:37has no single agent activity,
• 01:01:38does it can it have realistically a chance
• 01:01:41of being synergistic in a combination?
• 01:01:44Some people pointed to Vinito
• 01:01:45Clacks as the rule that this,
• 01:01:47but actually Vinito clacks as you
• 01:01:48said does have single agent activity.
• 01:01:50It's not much,
• 01:01:51but it does have activity and
• 01:01:52some people took a Victory lab
• 01:01:54with Magrolimab because it has
• 01:01:56zero single agent activity and all
• 01:01:58the fuss about the combinations
• 01:01:59and then the face reasoning.
• 01:02:00So so is your sense that if you
• 01:02:04have no single agent activity,
• 01:02:05can you really be synergistic
• 01:02:07in combination as a general?
• 01:02:09Yeah, I think it was like general question.
• 01:02:13I would probably be very worried about
• 01:02:15going to phase three with a drug
• 01:02:17that has no single agent activity.
• 01:02:19As you said the NOW class did have activity
• 01:02:21you know reduced blast in 50% of patients
• 01:02:24and the the data also in the front line
• 01:02:27setting where they did the bone marrow,
• 01:02:29they did seven days venetoclax pretreatment
• 01:02:31just single agent and they did bone
• 01:02:34marrow that was done in Australia and
• 01:02:36they also showed reduction or even like
• 01:02:38remission in about 50% of patients.
• 01:02:40So it does have single agent activity
• 01:02:42but also like different mechanistically
• 01:02:44because it's like a sensitizer, right.
• 01:02:46So you can, you know,
• 01:02:47think that even if you didn't
• 01:02:49have that single agent activity
• 01:02:50in combination you might have had.
• 01:02:52But I personally like I'm very
• 01:02:54worried that you know, I I'm,
• 01:02:56I'm not sure I would develop the drug that
• 01:02:59has absolutely no single aging activity
• 01:03:01and combinations, you know, going forward.
• 01:03:04I might be wrong.
• 01:03:06Thank you so much.
• 01:03:08Thank you everybody.