"Development of PET Radiopharmaceuticals for Brain Tumor Imaging" and "In Vivo Metabolic Imaging in Primary Brain Tumors"

February 02, 2022

Yale Cancer Center Grand Rounds | October 27, 2020

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00:00New Cancer Center grand rounds and
00:02actually we have a really interesting
00:05thematic presentations today,
00:07which is two of our faculty who
00:10are focused on imaging technologies
00:13in a way that I think is going to
00:17provide important insights into.
00:19Not only neuroscience but most
00:21specifically in brain tumors,
00:23and obviously for a disease like
00:25that novel imaging studies,
00:27I think are critical for true
00:29human in vivo research.
00:31Soum without further ado,
00:34let me introduce our first speaker,
00:37Doctor Jason Kai is an assistant professor
00:40of radiology and biomedical imaging.
00:43Jason did his postdoctoral work
00:45at University of Pittsburgh and
00:47then ultimately recruited.
00:49TL to be an assistant professor
00:52and his research group is focused
00:55on developing novel approaches of
00:57PET imaging for drug development,
01:00as well as the investigation of
01:02neurologic disorders and brain tumors.
01:05Jason received the bursts in
01:07Yellow award for his original work
01:10in nuclear medicine,
01:11and also the Arch of Foundation
01:13Research Award,
01:13which force which advances his
01:16novel research in neuroscience
01:18and Jason welcome and.
01:20Looking forward to your hearing about
01:22your work in brain tumor imaging.
01:25Thank
01:25you, thank you. Action so I'm
01:29gonna share my screen. OK.
01:37Here we go.
01:41Alright, are you looking at
01:42the right screen? Yes. OK, great.
01:47I'm very excited to be here
01:49to talk about our research in
01:52the context of cancer imaging.
01:54So our life, you know,
01:56spend a lot of time working on
01:58neuroimaging and tensor imaging.
02:00So neurology is a virtually
02:04crosstalk between these two fields.
02:07So I'll be introduce introduce
02:09in pet imaging very quickly.
02:11A little bit of a brain tumor.
02:14I believe Rene is going to talk about
02:18that like in more details in the next talk.
02:21And next I will talk about some
02:23some of the radio pharmaceuticals
02:25or pet users that are commonly used
02:28in clinical research or clinical
02:31management of brain tumors using pads.
02:34And lastly,
02:35talk about some of the new targets.
02:38For Brent tumor imaging,
02:40which are not specifically
02:42interested in us for us,
02:44you know as research lab.
02:47So first blue bus stoma is fatal
02:49disease with less than 10% of
02:50patients surviving five years after
02:53initial diagnosis and treatment,
02:55and 15% of all parental merge and
02:58half of the ugly omas is glioblastoma,
03:02there's still no early detection
03:05method available, so.
03:08No people in this world you are
03:11calling for new and better imaging
03:14measures manage this disease.
03:18So pat imaging. In a shell composed
03:22US 4 components.
03:23So first we need to have a pet
03:27scanner to detect all the packs
03:29signals and 2nd we need to have a
03:32patch razor or pet radiopharmaceuticals.
03:35We call it patch razor because we
03:37read missed the turn of very small
03:39amount of radiopharmaceuticals.
03:41The trace amounts and also
03:43because those molecules tend to
03:46be tracing the biological process
03:48or receptor protein and then.
03:51So it's patches are for for each.
03:54And next we need to have a quantification
03:57managers mathematical models to generate
03:59physiological parameters on this path.
04:02Imaging studies and the last and most
04:05important component is in clinical impact.
04:07So this is up to nuclear physicians
04:11to how to use these tools.
04:13The combination of the scanner,
04:15patch tracer and quantification
04:17measures to make an impact in
04:20patient and disease management.
04:25So we just published a mini review on
04:28the current video pharmaceuticals or
04:31patterns in brain tumor. This year,
04:34so this talk is mainly around this.
04:37Same from this review.
04:41So first the most classic
04:43patches are used for brain.
04:45Tumor is obviously a glucose
04:48and called effed floral deoxy
04:51glucose and 1st application of
04:55EFG happen to be in brain tumor.
04:59That's back in 1982.
05:02Parties several case reports actually.
05:06As you can see from the image here,
05:08the 1st and 2nd are contrasting
05:11Hung City images and you can
05:14see the the brain tumor mass.
05:17Indicated by enhanced mass.
05:19By this contrast city.
05:23And also from the patch
05:25you actually see a hypo.
05:30Because this happened to be a low
05:33grade brain tumors and later after
05:36after approved in 1997 and as
05:39you can see at the earliest time,
05:41the pass scanner has very
05:43low spatial resolution,
05:44is about 1.7 centimeter resolution
05:47and now we have dedicated brain
05:49PET scanners up with up to one or
05:52two millimeters spatial resolution.
05:56So after G as you see,
05:59it has a high background in the brain
06:02because the brain uses sugar as it's
06:05a major metabolism or energy source.
06:08You can see from the green
06:11matter higher uptake.
06:12Well I lower, but after you still
06:15useful for grading gliomas because
06:18for low grade or benign gliomas usea
06:22hypometabolism you have lower uptake
06:25in the brain region in the brain tumor
06:27region relative to the Gray matter,
06:29while at higher grade gliomas you have
06:33a higher optic for which is higher
06:36than Gray matter and white matter.
06:40With a global stoma,
06:42you can have even higher and also you can.
06:46You can see there's microsys
06:48car in the center of the tumor.
06:52So based on paper published in 1995,
06:54there's a cut off level for
06:57differentiating low grade from
07:00high grade glioma which is 1.5 for
07:03tumor to white matter and one zero
07:06point 6 for tumor to cortex ratio.
07:09Nowadays, because of the, uh,
07:12the fusion of pet with anatomical
07:15radiological imaging methods such
07:18as the city and actually you can
07:20use a contrast enhance and topical
07:23modalities to define the region of
07:25interest for the tumor to better
07:28quantify the FDG uptake.
07:32So because of the high background
07:35of sugar analogs, so people in this
07:38field have been calling for a pet
07:41imaging agents with lower burn uptake.
07:46So that turned out to be a amino acids,
07:48so amino acid analogues tend to have
07:52lower uptick in healthy brain tissues,
07:55while higher uptake in tumors
07:58because tumor cells overexpress.
08:00I mean, I'll type amino acid transporters.
08:04So the most advanced of C arguably
08:08is a missile in its carbon 11,
08:12labeled my selling,
08:13so this is essential amino acids that are
08:17taken by tumor cells while its uptake
08:21in healthy tissues or cells are limited.
08:25So it's useful in the clinic
08:28clinic to distinguish a tumor
08:32progression from radio necrosis.
08:34For example, in this in this case,
08:37from the anatomical images,
08:38it's it's pretty hard to
08:41distinguish these two cases,
08:42but from my selling is also
08:45called Matt from Matt Pat.
08:48You can easily tell the top cases
08:51a tumor progression while the
08:53bottom case is actually a radio.
08:55This.
08:59So besides, I mean the acid pat.
09:02There's also imaging agents derived
09:06from nuclear sites because nucleotides
09:10are used for DNA synthesis.
09:13And it's up taken into the tumor
09:16cells through, for example,
09:18this is a floral submitting I freaking
09:21labeled for submitting is a nuclear
09:24size up taken into cells by submitting
09:28kindness 1 and submitting kindness.
09:31One is over twice during the in the tumor
09:35cell because some of the DNA synthesis.
09:38Sides are involved in general
09:41in cellular proliferation,
09:43and they can correlate.
09:46Histological grade of brain tumors and
09:49its accumulation also correlates with
09:53the activity of summoning Chinese one.
09:56And it's a ideal tracer for
09:59imaging tumor proliferation.
10:01But also, but also because I felt is
10:04not actually it's not brain penetrant.
10:06It doesn't cross blood brain barrier.
10:09So in order to have any signal up take
10:12the tumors, BBB needs to be compromised.
10:15So it's not suitable for our
10:17lower create imaging.
10:21But nevertheless, it's it's.
10:22It's has its role in the tumor imaging pad.
10:27So from this case you can see the contrast
10:30getting contrast enhanced MRI images,
10:32which can clearly delineate
10:34the tumor regions,
10:35and you can see the hypermetabolism
10:37sugar metabolism in the center
10:40of the tumor and also my selling
10:44uptake in a larger area while found
10:47felt pad you can actually.
10:50See not only the tumor,
10:52but also the infiltration of
10:53the tumor to the brain region.
10:59So besides my sounding match,
11:02there are other amino acid analogs
11:05being used in brain tumor pet.
11:08For example, tossing and floral floral
11:14dopa F dopa F dopa is actually approved
11:18by FDA to image Parkinsonian syndrome
11:21back in 2019 because after reflects its
11:27accumulated in dopaminergic neurons.
11:30Neurons are damaged in Parkinson's disease,
11:34but but there are also a lot of
11:37efforts in applying F DOPA in brain
11:40tumor imaging because F DOPA is also
11:43transported into brain tumor cells
11:45through all type of transporters
11:49and once it's inside the cells,
11:51it's metabolize into DOPA and
11:54it's trapped in the cell.
11:57A recent relative recent Patricia for
12:01amino acids imaging is a floozy chlorine.
12:05This is this treasure is approved by FDA in
12:092016 for imaging recurrent prostate cancer,
12:13but they're still great effort in
12:16applying this treasure in global imaging.
12:21And actually the tumor uptake of F18.
12:26In quality well with.
12:29Bring to my images through night myself.
12:33Uhm?
12:35And it's actually useful when the MRI
12:38contrast enhanced MRI is non diagnostic.
12:41But still,
12:42based on the preliminary data we have
12:44in the following clinical studies,
12:46we can't tell whether the uptake
12:49of flu cycle is solely due to the
12:53recurrent tumor or perhaps some
12:56of the signals contributed from
12:58inflammation and other processes.
13:01So further studies is needed to establish
13:04the role of this treasure in the
13:07management of brain tumor in the clinic.
13:13So with that, I'd like to introduce some of
13:17the emerging imaging targets for brain tumor.
13:21So my interest in bringing my image
13:24and actually is originated from this
13:27part X Sigma 1 receptor imaging.
13:30So we were initially interested in
13:33using Sigma 1 receptor PET to study
13:36in your degenerative disorders and
13:39in one summer there was a visiting
13:42student from Germany and he brought
13:44in a product to use Sigma 1 receptor
13:48developed in their lab to image burn tumor.
13:52So to evaluate their imaging probe so
13:55we collaborate with John being slab.
13:57So this is gone down from his lab,
14:00generated you 87 look,
14:02which is a blue blastoma tumor
14:05cell and expresses luciferase.
14:08So we use valid methods to monitor
14:12the tumor growth over three weeks.
14:15After the tumor reaches a certain size,
14:20we scan them by using pet small animal pet.
14:26Pet city and we used 2 pets
14:30and their natural.
14:34From the pet images, we can tell
14:36that rumor update is significantly
14:37higher than the rest of the brain,
14:39while the two updates decrease overtime,
14:42eventually getting lower than the
14:45healthy brain tissue. For each.
14:50Natural nurse and found the T2 MRI.
14:53We can clearly visualize the tumor
14:55so we can analyze the region of
14:59interest for the tumor uptake.
15:04So this tells us the Sigma 1
15:06receptor expression in healthy
15:08brain is also significant,
15:10which may similarly to FG pad,
15:12complicates the PATH imaging data analysis.
15:15So this is also confirmed by doing
15:17nonhuman primate patting imaging.
15:19So Sigma 1 receptor uptake in healthy
15:25brain regions significantly overtime.
15:29So the question now is to identify
15:32by marker for global stoma with low
15:35expression in healthy brain tissues.
15:38So that turned out to Park Park is
15:43the Poly ADP Ribosyl polymerase pop.
15:46One is the DNA repair enzyme.
15:49It's always provides in blastoma
15:52with overall lower expression
15:54in healthy brain tissue.
15:56So in that sense,
15:57it might be an ideal image
15:59engines for globalist tumor,
16:01imaging and parks functions to
16:04recognize DNA damage and recruit
16:07proteins to repair single strand or
16:10even double strength daily damage.
16:13There are multiple active clinical trials
16:16going on actually targeting part as a
16:19therapeutic target in global storm,
16:22so up at imaging agent targeting
16:24Park could be also helpful in
16:28facilitating the drug development
16:30or stratify patients for park
16:33targeted images therapeutics.
16:37To evaluate any imaging agents
16:40before we do clinical imaging study,
16:43we need to evaluate those imaging
16:46probes using animal models.
16:48So this is work done by Carney
16:50and colleagues published in 2018.
16:54They actually surveyed part one
16:57expression over a panel of human
17:00PDX small cell lung cancer PDX,
17:03and together with healthy tissues,
17:06found rodents.
17:07As you can see,
17:08the park is generally positive and
17:11highly expressed in these PDX tissues
17:15as well as in spleen of the animal,
17:18while its expression in brain
17:20tissue is relatively low.
17:24So further, they injected a like
17:28rip derived TARP imaging pad
17:31agents into this PDX models.
17:34They were able to.
17:36Identify the tumor uptake
17:38overtime and compare it with the
17:40muscle as a reference region.
17:42Normally muscle has because muscle
17:44has very low uptake of the tracer,
17:47indicating slow part expression in muscle.
17:52And the park image agents showed
17:55quick uptake into the tumor,
17:57which is slowly decrease overtime
18:01and mass tumor to muscle region
18:03reaches the highest level at 2
18:06hours post Twitter injection.
18:10So by using pad imaging
18:12they were able to study.
18:15They found kinetics of
18:17the library derivatives.
18:20I did about the same time back in 2018.
18:24Another group at Upenn and
18:27Studies another park,
18:28Paddington agents,
18:30which is derived.
18:34From a different scaffold,
18:36they name it F18 FT.
18:38So they did first in human study in.
18:42They recruited 20 patients.
18:44And scan them at baseline and the
18:47patients underwent surgery so they
18:49were able to collect the tissues to
18:53correlate the packaging results with
18:55the immuno histo fluorescence results
18:58as well as autoradiography study.
19:02So in this study they actually showed.
19:06A panel of parks specific uptick in the
19:09tumor by PAT as well as a immunofluorescence.
19:13And there's strong correlation between
19:16values and the fluorescence results,
19:19as well as between out radiography
19:23signal and fluorescence signal,
19:25but the part?
19:27Expression level doesn't correlate with PAT,
19:31so FG cannot be used in place
19:33of park imaging.
19:37So about earlier this year,
19:39there's they expanded their
19:42clinical trials of power pat
19:45into a breast cancer patients.
19:51However, all of the park imaging agents.
19:55We have currently do not penetrate
19:57intact blood brain barrier so that
20:00limits its application in brain tumor.
20:06And this is confirmed by their nonhuman
20:08primate, pet brain imaging study.
20:12So we took a look at the
20:15pharmacokinetic information of
20:17the current park inhibitors and.
20:22Decided to pursue base
20:25scaffold for Patty medium,
20:28hopefully to identify a brain penetrant.
20:31Potting medium agents for park.
20:34So in that direction, so we have.
20:38I don't know if I'd and synthesized
20:41lead park imaging agents derived from.
20:45And did a pilot study in
20:48collaboration with Hank for memory.
20:51Using their RG2 rank mode burn to more model,
20:54we were able to.
20:56Image CRD 2 tumor here the baseline
21:00scans using the power pad imaging
21:04agents and for this one we pre
21:07injected the animal with a code.
21:11Well, if a rate which is also
21:13part specific molecule that can
21:16compete with Patrick to displace
21:19a tutor uptick in the tumor.
21:23So after semiquantitative analysis.
21:25We can tell from the average values from 30
21:31to 60 minutes post tracer administration.
21:35The tumor optic is about one
21:38after the blocking drug update
21:40was decreased to about 0.5,
21:43indicating the new park padding
21:45medium tracer actually really
21:47target Park in vivo as they ban to
21:49the same target as a Liberator,
21:51blocking drug at the same time we
21:54look at the control later role,
21:55which is presumably to be
21:57the healthy brain tissue.
21:59And it showed relatively lower uptake.
22:02Send a tumor and the blocking doesn't
22:06have significant effect over there.
22:08So here's the tumor to contralateral
22:11ratio and at baseline it's about 2.5
22:14after blocking drops to about 1.5,
22:16indicating about 46% blockade from the.
22:23To validate the path image data,
22:25we perform pilot biodistribution study.
22:29We look at the tracer distribution among
22:32the different different tissues of animal.
22:38Not surprising me that Rooster has
22:41high spleen uptake because spleen is
22:44another large organ and that's positive.
22:47Also, it's a blocked by the.
22:51And consistent with the pattern medium data,
22:54we see high uptick in the tumor,
22:57and it's blocked by the brick as well.
23:03Further analysis of this pilot data
23:06indicates very high spleen to blood ratio
23:11and also very high tumor to blood ratio.
23:15For the power quality of regions and it
23:18also shows some extent of the brain uptake,
23:21which is seem to be blocked by the cold drug.
23:25So further study confirmative study
23:26needs to be done to see if this traitor
23:30actually goes into the intact brain or not.
23:35OK, the next part,
23:37like the next image in target,
23:38I'd like to introduce is PDL one.
23:40I think for this target this is
23:42probably the targets that doesn't
23:44need much introduction PDL 1 so
23:47we do have PDL 1 targeted PET
23:50imaging tracers in this field.
23:53Dave Donnelly published paper in 2017
23:56about their protein based PDL 1 Patricia.
24:05Nine, six, 182 so the use a simple xenograft
24:10with PD L1 positive tumor on one side and
24:13PDL one negative tumor on the other side.
24:16So they did the baseline scan without
24:19blocking agents and they did a blocking scan
24:21that you can see after blocking agents.
24:24The Twitter uptake was diminished
24:26to the same level of the unspecific
24:29update to the same level of Cpl.
24:31One negative tumor uptake.
24:33Well, the baseline scan showed higher uptake,
24:37so they also did autoradiography.
24:39This is in virtual autoradiography study.
24:44Not not only look at this too,
24:47they don't draft silence.
24:48They also look at some some human
24:51tissues and they sell like higher PDL.
24:53One expression in those human tumor tissues.
24:57So with that data they translated
24:59their imaging probes to 1st in
25:01human study they they chose non
25:03small cell lung cancer as there.
25:05Patient population in that study,
25:09published in 2018.
25:11They actually compared with PDL one pad and
25:15another at the only making nine labeled.
25:18If I look at the PD one pad so those
25:23three imaging modalities can all detect.
25:28Non small cell lung cancer,
25:29not you,
25:30but with the heterogeneous imaging patterns
25:34indicating those three modalities are
25:36actually complementary to each other.
25:39They provide different information
25:41on the tumor metabolism and PDL.
25:44One expression as well as PDL.
25:46One expression.
25:51Also they showed one case where
25:53there's a tumor metastasis
25:55because the tumor metastasis,
25:57so it could be the low PDL expression
26:00over there, or it could be the
26:02more intact blood brain barrier.
26:04So in order to apply PDL 1 packaging
26:08in in tumor imaging or glioma patch,
26:12we initiated a project to
26:15develop brain punishment.
26:17PDL 1 patting million agents
26:19based on small molecules.
26:21So this project at early stage I don't
26:24have animal data to share with you,
26:27so do not just say very briefly the
26:31process for discovery and development of
26:34radiopharmaceuticals or patch research.
26:37So if you look at this project
26:39it's actually very similar to the
26:41R&D process of a therapeutic drug.
26:43You need to identify a target or
26:46clinically relevant biomarkers
26:47and you need to do met Cam to
26:50develop small molecules or.
26:51Micro molecules specific binding to
26:54the target after initial essay and in
26:57vivo essays using patent distribution.
27:03You can move on to the toxicity
27:05and dosimetry study and file and
27:08application after doing clinical trial,
27:10initial validations and clinical
27:13trials finally reached to FDA approval.
27:17So I'd like to use the last few
27:19minutes to update you the latest
27:22advancement in the past scanner,
27:24because pass scanner is a critical
27:27component in the pet imaging research.
27:31So very excitingly recently we saw
27:33a prototype for total body pad,
27:35so traditionally the path scanner needs
27:38to move the bed to get the whole body.
27:41PET imaging study done,
27:42but with a total body PAT
27:45we can collect all the.
27:46Emission signals from the patients,
27:49so that means significantly.
27:52Increase some detection sensitivity
27:55and we which allows much lower
27:58dose for for the patient.
28:02So supposedly we can reduce the.
28:08The real pharmaceutical injection.
28:09The dose by 40 fold.
28:11This means the whole body PET scan will
28:15will cause 0.15 million safe dosimetry.
28:19Well, the national background.
28:22Every year, 2.4 million safe and
28:25long Trip international round trip
28:27is about 1.1 million save this means
28:30the whole body pet can reduce the
28:34dosimetry to almost equivalent to
28:36a round trip international flight.
28:40And also with the whole body
28:41pet scanner system,
28:42we can study the diseases
28:44at the systemic level.
28:46So looking at the cancer throughout the body.
28:52So in summary. Pat's imaging
28:56and potentially application in
28:59glioblastoma is to demonstrate the
29:01final type and disease severity
29:04correlations and hopefully you will
29:06be able to discover new therapeutic
29:08targets based on morgue imaging,
29:10clinical imaging studies and it's also
29:13very helpful in the drug development
29:16process in demonstrating the
29:19penetration and pharmacokinetics of the
29:22experimental drug in effect compartment.
29:25It can be used to quantify
29:26commutate from Cortana,
29:28mix by doing receptor occupancy study
29:31to maximize the the dose range to be
29:34used in efficacy clinical trials.
29:38And also how could be useful for
29:42patients stratification and to
29:44evaluate therapeutic effects?
29:46And in the clinic pet can be used
29:50for diagnosis or prognosis as well
29:53as tracking disease progression.
29:55I finally achieve precision medicine,
29:59so at last I'd like to acknowledge
30:01my group and staff,
30:03faculty and students at your pet
30:06center or internal and external
30:09collaborators and or finding
30:11agents for supporting our research,
30:14and this is picture we took last year
30:17and this is what we look at this year.
30:22Well, Jason, thank you.
30:24It was a really terrific review of,
30:27you know, novel approaches to imaging
30:29both for clinical care and research.
30:31And yeah, thank you for changing
30:34the context of your research group
30:36photo in terms of the current world.
30:39You know, Jason, we're at, why don't we?
30:42Why don't I suggest that for
30:44folks who have questions for you
30:46to direct them to you offline?
30:48Just 'cause we're at the we're a
30:50little late in the time and I want
30:52to make sure there's time for.
30:54For Zach but Jason thank you for us.
30:57Superb presentation again.
30:59I invite people to submit send
31:02questions to Jason to his email,
31:04but let me now turn to our.
31:06Our second speaker.
31:07Did Doctor Zachary Corbin,
31:09Zach as many of you know as an
31:12assistant professor of neurology, he.
31:14Received his medical degree at Yale
31:17and thereafter did his residency
31:19training at the University of
31:21California at San Francisco,
31:23ultimately being recruited back here to
31:27join the faculty in neurology and neurology.
31:30Zacks interest beyond CNS
31:34malignancies has been in research,
31:37most notably in understanding the
31:39biology of brain tumors through
31:42novel approaches to imaging,
31:44and.
31:45Particularly the metabolic changes
31:46that occur in these tumors.
31:48So is Zach thank you for agreeing
31:50to present and really interested.
31:52Really excited to hear about
31:53your work and Jason if you could
31:55stop sharing your screen.
32:04Perfect thank you very much. Let me start.
32:08Sharing my screen.
32:16OK. Doctor Fuchs thank you
32:19so much for the introduction.
32:21Can everyone hear me and see my screen?
32:23Yes and thank you very much,
32:26Jason and thank you for the introduction
32:28or thank you for the invitation.
32:31So I'm one of the neuro oncologist at Smilow
32:34and it's my privilege today to talk about.
32:38In vivo metabolic imaging of primary
32:40brain tumors and what a great
32:43segue or transition to move on.
32:45I'm going to start really by giving.
32:48Some background clinical
32:50background on glioma,
32:52clinical treatments and
32:54limitations of glioma,
32:55and specifically glioblastoma
32:56as was introduced.
32:58I'm going to talk a little bit more
33:01specifically about pseudo progression.
33:03Which is something that Jason Jason
33:05mentioned and also has been discussed
33:07in this venue by Doctor Chang with
33:10metastatic disease in the brain.
33:12I'm gonna talk about metabolism and
33:14cancer and the Warburg effect in
33:16particular as a prominent metabolic
33:18change that we could potentially image.
33:20The transition to methods results.
33:24And our current investigations things
33:25we can show you now and things we're
33:28very excited about showing you soon.
33:30In particular,
33:31I'm going to talk to you about something
33:33that we call the Warburg index,
33:34which we created here at Yale.
33:37And then future directions and things.
33:39We're looking forward to sharing
33:41with everyone in the future.
33:43So to move forward and talk about
33:46some background. I think that.
33:49Glioma has a profound impact.
33:52It's a relatively rare disease.
33:54But the public burden is substantial, right?
33:58I when thinking about the disease,
34:00I like to think about important.
34:03Public events that have happened recently,
34:05so this is.
34:08Ted Kennedy, President Kennedy's brother.
34:11Who died of glioblastoma as
34:14Senator of Massachusetts in 2009?
34:16And this is Beau Biden.
34:19Vice President Joe Biden son.
34:22So he was.
34:23Previously, Attorney General Delaware, but.
34:26He did die of what is known as an
34:29aggressive primary brain tumor,
34:32while his father was vice president
34:34of our country.
34:36And this is John McCain.
34:38Who died of glioblastoma as
34:42senator from Arizona?
34:44And so you know.
34:46That was a good introduction to
34:49what is a disease that has an annual
34:52incidence in the US of 20,000.
34:54Is is glioma in general and glioblastoma in
34:57particular has an annual incidence of 11,000.
35:01Actually almost 12,000 / 11,000.
35:04It's the most common primary
35:06malignant brain tumor.
35:08As Doctor Kai already mentioned,
35:11and its five year relative survival,
35:13it has increased recently.
35:14I'm an optimist, so this is an
35:18improvement at 6.8% in five years.
35:20Only a few years ago we were
35:22discussing numbers in 5% and so.
35:25We're moving forward,
35:27but we have a lot of movement to do.
35:30Glioblastoma is a profound disease,
35:32frequently at presentation.
35:34This is a case.
35:36That I cared for when I was
35:38a fellow at Stanford.
35:40This is a relatively common
35:42scan we see here you have.
35:45MRI,
35:45gadolinium enhanced T1 sequence
35:48where you can see boundaries
35:50of blood brain barrier,
35:53breakdown of the primary tumor.
35:55This is flare processed T2 sequence.
35:59Axial projection of the MRI.
36:01We can see some changes
36:02surrounding the tumor.
36:03This is a substantial tumor
36:05with lots of Mass Effect.
36:06You can see shifting of the normal brain.
36:09This patient had relatively mild symptoms.
36:12If I recall he had visual field
36:15changes and he had a neglect syndrome,
36:17but actually really presented
36:19mostly because his.
36:21Family brought him in and that is true.
36:23This is a sudden and dramatic disease,
36:25but can actually be relatively
36:27subtle as well to some patients,
36:30which is remarkable.
36:33And I like to show this slide
36:35for three reasons really.
36:37So despite what is really
36:40an absolutely remarkable,
36:41as it's a privilege to talk here.
36:45Research and clinical endeavor to improve
36:48care for this category of diseases.
36:51We still have a standard of
36:53care in glioblastoma from 2005.
36:55This is the Stroop paper,
36:57also called the Spook Protocol from 2005,
37:00and it demonstrated that patients with
37:03glioblastoma have improved outcomes
37:05when they are treated with radiotherapy.
37:07It's really chemo radiation radiotherapy
37:09plus temodar at the same time, followed by.
37:12Excuse me, temozolomide after radiation.
37:16And they have improved outcomes
37:18compared to radiation alone.
37:21But as I said,
37:21I like to show a few things here.
37:23So we have a great deal of patients
37:25who have died and very quickly and
37:28this is relatively noisy out here,
37:30but we still have a number of
37:32patients to measure the effect so
37:34you can see that there's a lot
37:36of room to grow as I mentioned.
37:38But in addition,
37:38you can see something else that's
37:40interesting, which is that.
37:41There are a number of patients
37:44that survive and a long time years.
37:47And it's very difficult to predict as
37:50doctor time mentioned at the start.
37:52Who is going to come from here
37:54and still live?
37:55We don't have prognostic or
37:58diagnostic ways of determining this.
38:01So in order to discuss another related
38:06but somewhat complementary fact of care for.
38:10Brain tumors currently is the delayed
38:13results of other clinical trials in
38:15patients who have tumors that are
38:17less aggressive than glioblastoma.
38:19So these are the results of the RTOG 9402.
38:24Clinical trial.
38:25That really targeted a moderate
38:28severity brain tumor,
38:30and anaplastic oligodendroglia OMA
38:32and oligo astrocytoma although oligo.
38:34Astrocytoma is a relatively antiquated term.
38:38In this.
38:39Protocol enrolled patients,
38:40and similarly to the Stu Protocol
38:43patients received either chemotherapy,
38:45this time with PCV,
38:46chemotherapy with radiation,
38:48or radiation alone. And you can see.
38:50Approximately 10 years in 2006,
38:53approximately 10 years after
38:54the study was started,
38:56there was no indication as
38:58to which was superior.
39:0010 years later,
39:01almost 20 years after the study began,
39:03you can actually see a signal,
39:05and by this analysis it demonstrated
39:07that patients do better with PCV
39:10with radiotherapy as compared
39:11to radiotherapy alone.
39:14So we have.
39:16Two processes going on where you
39:17have a substantial burden of a very
39:19aggressive disease and difficult to
39:21predict long term survivors in that disease.
39:23And then less aggressive tumors we have.
39:27Prolonged 20 years,
39:28potentially wait between when we
39:30institute a standard of care or or
39:33when we are trying to define the
39:35same care when we have results that
39:37help us with that standard of care.
39:39So this is really good fodder for
39:41exactly what the context today
39:43is for other ways.
39:45Biomarkers of measuring this disease.
39:48So I want to switch gears for a second
39:50and also discuss pseudo progression.
39:51Specifically,
39:52this is another case that was brought
39:54up to me when I was a fellow at
39:56Stanford. This patient had a glioblastoma.
40:00He underwent treatment and then this is very
40:03similar pictures as I've shown you before,
40:05so gadolinium enhanced MRI and flare
40:08T2 MRI and you can see tumor here.
40:12So the patient actually
40:14had growth of the lesion.
40:16And it was raised whether this
40:18lesion wasn't true tumor progression,
40:21or whether it was pseudo progression.
40:23Pseudo progression,
40:24largely in necrosis,
40:25but really a response,
40:26probably by the tumor and also the brain
40:29to treatment that we give the patient.
40:31And so standard of care
40:34studies include FDG PET,
40:36which we've heard a lot about in this study,
40:37and you can see the background,
40:39as was mentioned, is quite bright.
40:41This is all normal brain.
40:43But in the area of this tumor,
40:45you can see that there is uptake,
40:46and so this is hypermetabolic.
40:47It was felt that favored tumor,
40:50and so this patient went to surgery.
40:52Unfortunately,
40:52surgery showed that this patient had
40:54in crisis with his pseudo progression.
40:56So it's very challenging to deal with
40:58pseudo progression in primary brain tumors,
41:00especially in the setting of the need
41:03to have a large surgery to confirm.
41:05So one of the potential areas to
41:08expand our knowledge is imaging and
41:11really imaging has moved forward with
41:14the overall understanding of cancer,
41:17which has been maybe 100 years
41:19ago in anatomical disease,
41:20tumors, balls that are growing
41:23to physiologic disease,
41:24tumors that acquire blood vessels
41:26and other changes as they grow and
41:29become more aggressive to really,
41:31what is a metabolic disease
41:33where they are fundamental,
41:34likely metabolic?
41:35Changes that might be the night
41:37is of cancer and certainly are
41:40associated with aggressive disease.
41:42Imaging is really move forward
41:44with our understanding.
41:45Anatomical and 1st we were able to,
41:46just as we showed here.
41:49See the tumor ball.
41:50Then we learn much more about the
41:52tumor by things like perfusion imaging,
41:54which can tell us a great
41:56deal about the heterogeneity,
41:57especially of aggressive
41:59primary brain tumors.
42:00And metabolic imaging now has
42:02become at the forefront where we
42:04might be able to do many things.
42:05Potentially, I'll show you.
42:07Do some prognosis and diagnosis,
42:10but in addition,
42:12potentially treatment effect measurements.
42:14So to understand a little bit more about
42:16how we could use metabolism in this way,
42:18I want to talk a little bit
42:20about the Warburg effect.
42:21In particular,
42:22this is probably the most famous
42:24metabolic change that is known to
42:26occur in cancer and in primary
42:27brain tumors in particular.
42:29So to take everyone back to biochemistry,
42:31here is a cell,
42:32and this is the cell membrane,
42:34and so there's glucose outside the cell,
42:35and as glucose comes into the cell,
42:37one of the large junctures is pyruvate,
42:39and pyruvate can get processed basically
42:43into oxidative phosphorylation.
42:44In One Direction.
42:45And in that direction,
42:47is mediated largely through the mitochondria.
42:49You have evolution of CO2 in
42:52the aqueous cytosol.
42:53It really transfers back
42:55and forth to bicarbonate.
42:56However,
42:57glycolysis is also a potential
43:00route for for processing
43:02of pyruvate, and the end result
43:05is lactate in glycolysis.
43:07And so the Warburg effect is in the
43:10absence of any other stressors,
43:12including normal blood flow,
43:14tumors are known to favor glycolysis.
43:16They shift to lactate,
43:18they produce more lactate,
43:19and they undergo less
43:22oxidative phosphorylation.
43:23And in this diagram,
43:24as you move further to the right,
43:26you have more Warburg effect.
43:29This preference for glycolysis
43:31seems unusual initially, however,
43:33there's really a lot of reasons
43:35why tumors may benefit hydrocarbon
43:36backbones and also redox species
43:39may be usable in biosynthesis,
43:42especially through the
43:43pentose phosphate pathway,
43:45to produce more tumor.
43:46In addition,
43:47energy production and also
43:49really more simpler energy
43:51apparatus is less vulnerable to
43:53the oxidative damage that occurs
43:55in tumors and in normal tissue.
43:57The resulting acidic environment
43:59is important for many physiologic
44:01changes related to tumor,
44:03including tumor invasion.
44:07Excuse me and also immunosuppression
44:10so immune cells less able to attack the
44:12tumor in the acidic environment and also
44:14normal tissue that's able to survive.
44:17It's been linked to tumor
44:19aggressiveness already.
44:20And so really is a great target to image.
44:24So to move forward to how we would image
44:26them with those methods and some results
44:28we have as well as current investigations.
44:30So first I'd like to talk about the deuterium
44:33metabolic imaging and then the Warburg index.
44:35So deuterium metabolic imaging.
44:36Really the credit goes to
44:38my colleagues at Yale.
44:39Dr Defeater, Hank debater as well as
44:42Doctor Robin de Graff who have really done
44:45an amazing job in developing this tool.
44:48We are able to give patients
44:50due to rated glucose,
44:51so this is heavy water or sorry,
44:54heavy glucose.
44:55Basically protons with a neutron attached.
44:58Patients can drink them and it
45:00actually goes into their cells
45:01over the course of about an hour.
45:03And we can see due to rated lactates
45:06evolving in tumor and we can see the
45:10evolution through oxidative phosphorylation
45:12of glutamate and technically it
45:14includes glutamate and glutamine signal.
45:17And as you can see,
45:19the shifting more towards glycolysis.
45:22You can actually image a really direct
45:24bound worker of the Warburg effect.
45:27So once again, so you have due
45:29to rated lactate over glutamate,
45:30really glutamate glutamine is related to
45:33glycolysis over oxidative phosphorylation,
45:35which is the Warburg effect.
45:38So we were able to start with multiple
45:41different types of brain tumors,
45:43and I'm going to show you a few today to
45:46discuss the tumor I mentioned before.
45:48That medium grade tumor and
45:51anaplastic oligodendroglia.
45:52Here you have a patient.
45:54This is flare. This is post contrast.
45:57You can see residual chamber.
45:59The patient has two voxels that are shown
46:02here in the Mr spectroscopic spectrum,
46:05and so you can see the glucose
46:07is measurable in both Spectra,
46:10and you can see in the map that
46:11you can see lots of glutamate and
46:13glutamine evolving in the normal brain,
46:16so this is really wonderful this tumor.
46:18So the black,
46:19sorry the red voxel showing you this
46:22tumor is producing glutamate and
46:24glutamine through oxidative phosphorylation,
46:26similar to perhaps normal brain and really.
46:29Lactate measurement would be out here.
46:30We don't see the lactate in either side.
46:34One of the reasons why this tumor
46:36may actually have a more favorable
46:38character is the idea expectation,
46:40which is famous all over the world.
46:43Many different cancers,
46:44including glioma,
46:44and we have one of the world experts
46:46and IDH mutant glioma at Yale
46:48which who is one of my mentors.
46:50Dr Bendure Ranjit bindra.
46:53Has really been able to help me
46:56understand this better isocitrate and
46:58ideates wild type pathology or sorry
47:02Physiology produces alphabetically
47:04rate and with the IDH mutation
47:06that occurs in tumors,
47:07there's a hetero diamond and a
47:10heterodimer produces 2 hydroxy butyrate.
47:12This has been called a onco metabolite,
47:15which is a metabolite that
47:17may actually be involved in
47:19the production or the
47:22continuation of tumorigenesis.
47:23Downstream to two hydroxy
47:25glutarate in IDH mutant,
47:27pathophysiology is methylation changes.
47:29DNA hypermethylation in particularly
47:31MGMT methylation in gliomas,
47:33but also histone methylation.
47:37So I actually had the privilege of caring
47:39for what is a relatively rare patient
47:41who is an IDH mutant glioblastoma and
47:44we were able to actually image the
47:46tumor with deuterium metabolic imaging.
47:48This is prior to the patient having surgery,
47:50so this is really a perfect case
47:53and so with this case we can see
47:55here is the recurrent tumor.
47:57This is once again an idea, glioblastoma.
47:59You can see that post gadolinium
48:01scan is showing you tumor there.
48:03This is evidence of bleeding,
48:06which is common.
48:07And this is evidence of diffusion
48:09weighted changes, which is also common.
48:11I wanna call your attention
48:12to voxels one and three here,
48:14which are up here.
48:16These are within the tumor.
48:17And you can see the maps that are
48:19generated by deterring metabolic
48:20imaging are really marvelous.
48:22They show that glucose is
48:23going everywhere in the brain.
48:24They show that glutamate and
48:25glutamine is being produced
48:26by oxidative phosphorylation,
48:28as is expected in the normal brain.
48:29And it's really a totally different
48:32picture over the brain tumor.
48:33You can see this is the Warburg index,
48:35lactate over glutamate.
48:36Glutamine is a very large peak over
48:39the tumor and here you have the lactate
48:42visible on these spectrum and you can see.
48:44That there is a glutamate glutamine peak.
48:46It's a little easier to see with voxel one,
48:49so I'm going to call your attention
48:51in particular to voxel one,
48:53and I'm going to show you an IDH
48:55wild type of much more common
48:57glioblastoma that we were able to image.
48:59Call your attention to two voxels in
49:01the spectroscopy so you can see there
49:03is 2 which is within the tumor and
49:05there's one which is within normal brain.
49:07No lack tating the normal brain,
49:09lots of glutamate and glutamine in the
49:10normal brain, but lactate and glutamate,
49:12glutamine really within the tumor.
49:14Very little within the tumor,
49:15almost noise.
49:16But a very large Warburg effect.
49:21This is really an N of 1 experiment
49:23but it is very intriguing to see
49:25that there is more lactate and
49:28almost no glutamate and glutamine
49:29in the IDH wildtype yield estimate
49:32compared to much more even.
49:34Presentation and ideates mutant.
49:36We have Western ma.
49:37So we've developed a theory that
49:40we're very excited about that
49:42really the Warburg effect may be
49:44blunted or muted in an IDH mutant
49:47pathophysiology such that it displays
49:50metabolism more like normal brain.
49:53Where oxidative phosphorylation occurs.
49:56To a greater extent than
49:58in a idea 12 type tumor.
50:00So you've heard a lot about today,
50:03FDG pets, just to go briefly,
50:06the way that we would use this to help
50:08us with a clinical tool that might
50:10show the Warburg effect right now.
50:12Really,
50:12the the deuterium about imaging is wonderful,
50:15but really its preclinical technology.
50:19We could actually use potentially
50:21EFG patent FDA approved study.
50:24Its phosphorylated by hexokinase as
50:26it comes into the cell but then really
50:29it kind of represents glucose demand.
50:31For my purposes,
50:32I'm referring to it as the representation
50:35of oxidative phosphorylation or from
50:38the call of all energy into the tumor.
50:42We are combining that it's a multi
50:44modality test so the patient also will
50:47receive magnetic resonance spectroscopy,
50:49this time without a stable isotope
50:52measure like the deuterium and
50:53we'll be able to measure lactate
50:56which we can measure in the clinic.
50:58Actually in brain tumors.
51:01In the research context,
51:02we can also measure 2 hydroxybutyrate,
51:05which will be very interesting in this study.
51:07To correlate the IDH character
51:09of the tumor if you will,
51:12and the the other measures
51:14including the Warburg index.
51:16So the Warburg effect being measured
51:18with a multi modality image where we
51:21have lactate by Mr spectroscopy over
51:23the standard uptake value with dog pet
51:26and we are saying that that should
51:28be relatively equal hopefully to
51:30glycolysis over oxidative phosphorylation.
51:32Which is the warburger connectbot.
51:33We're labeling that the Warburg index,
51:35'cause this can be a tool that
51:38we could use now in the clinic.
51:40So we're looking forward to starting
51:42soon as we transform into a normal
51:46process of enrolling patients and
51:48observational clinical trials.
51:50Will have cohorts of 17 and 1788
51:54mutant gliomas and 98 well take
51:56llamas and will be performing marked
51:59prosperity imaging with protons,
52:01no label and measure lactate in
52:03two hydroxy glutarate and all of
52:06these patients and we will also
52:09perform FDG PET and and determine
52:11the sort of overall glucose demand
52:14energy demand from the tumor.
52:17Hopefully we'll be able to enroll
52:20these patients in more technical
52:22studies where we'll have really a
52:25research standard of the Warburg
52:26effect through things like the
52:28deuterium metabolic imaging stable
52:30isotope methods at the same time we
52:32all work together in Doctor Defeaters,
52:34one of my closest collaborators.
52:36And we will then follow this
52:37cohort of patients to produce our
52:39own clinical outcome measures.
52:41Especially interested in progression
52:43free survival and overall survival,
52:45which will be diverse in this
52:47group of patients where
52:48some patients will have an IDH
52:50wild type tumor more similar to a
52:52glioblastoma as I've shown you here,
52:54and some will have an idea,
52:55it's mutant chamber more similar
52:57to these long term patients that
52:59have very slow growing tumors.
53:02We will also through collaborations
53:04with Doctor Marat Daniels.
53:06Laboratory be able to perform
53:08whole genome methylation studies
53:10in all of these patients.
53:12So we'll have.
53:13An extraordinarily diverse and
53:15deep data set where we'll be able
53:19to potentially use preclinical
53:20Warburg effect measures to compare
53:23to Clinical Warburg index measures.
53:25Compare both of these measures
53:27to clinical outcomes,
53:28and then also in a vein of
53:31precision medicine implications.
53:32Be able to show exactly how much
53:34perhaps 2 hydroxy glutarate is being
53:36produced by the IDH mutant pathophysiology.
53:39And then what the implications to
53:41the methylome and the methylation
53:43of the genome is?
53:45So future directions we have actually
53:48recently been able to to image a
53:52patient within their treatment.
53:53So I've shown you once again,
53:55IDH mutant glioblastoma and
53:56I've shown you idh, wildtype,
53:58Leo Lester,
53:59mother relatively similar appearing.
54:01If you're not looking at the
54:02spectrum per say.
54:03Looks like very large warburger effects.
54:05Classic aggressive tumor.
54:08We had a patient who had a glioblastoma
54:10shortly following chemoradiation and
54:12when we imaged this patient we were
54:14unable to detect the word with effect on.
54:16This is very exciting.
54:18We potentially have not only implications
54:21to diagnostic and prognostic implications,
54:24as I was mentioning before with
54:26the Warburg Index clinical study.
54:27But now we have the potential to follow
54:30the same patient during their course.
54:32Where perhaps there are dynamic
54:34changes within the tumor.
54:35Perhaps this is just a time when we,
54:37when we caught this tumor and it was less,
54:39had less expression of the Warburg effect.
54:42But perhaps we're able to modify
54:44the Warburg effect and perhaps
54:45the aggressiveness of the tumor.
54:47With treatment that we do,
54:49and really if we can find that this
54:51is what we're really targeting and not
54:53the changes that can be so confusing.
54:56For example with pseudo progression.
54:58Then that's a very exciting frontier,
55:00so we're hopeful with the
55:02translational award moving forward,
55:03that we'll be able to scan some of
55:06these patients longitudinally both
55:07before and after chemo radiation.
55:10But in addition,
55:11along the way we scan patients
55:12in the clinic every two months.
55:14And so if we could potentially get
55:16metabolic imaging for all of these patients.
55:19Then it would potentially change
55:22our management fundamentally.
55:24I want to thank lots of people
55:26for all of this effort.
55:28It's definitely a village doing
55:30translational neuro oncology.
55:32This is really my laboratory size.
55:34My current research assistant and
55:37I have alumni who are already at
55:41Duke and NYU and medical school.
55:44I'm extremely grateful for the
55:46support I've had here through
55:48the Y CCI Scholar award.
55:50Also,
55:50my collaborators are A1.
55:52I'm grateful to Doctor Fuchs and
55:55to the Cancer Center.
55:56As well as just a multi institutional
55:59collaboration Dr Wrecked
56:00one of my mentors from Stanford.
56:02All of these individuals.
56:03It's not even a complete list at Yale.
56:05Really need no introduction,
56:07but especially grateful for this
56:09talk for contributions from Doctor
56:11Defeater and Doctor Rothman,
56:12and I want to thank you very
56:14much for all of your attention,
56:16and I think this is time for questions.
56:19Derek, thank you. And yes, we do.
56:21Actually, it's a great talk and
56:22and we do have time for questions.
56:24If if individuals want to submit
56:26that on the chat, so is Zach.
56:28Let me ask you given the
56:29the the thrust of your work,
56:31are there potentially?
56:35Developing on or ongoing targeted approaches.
56:39That would sort of focus on metabolic
56:42pathways coming along that your technology.
56:45Your assessments would actually be
56:47informative for or and or does this
56:50potentially OfferUp new targets.
56:52Well, I think it's a great.
56:53It's a great question and and I think.
56:57There's a couple ways,
56:58so actually I VH mutation targeting
57:01has really gone both ways.
57:02In our field it has been proposed
57:05that IDH mutant pathophysiology
57:06should be blocked with an inhibitor.
57:09And there's current clinical
57:11trials in that vein.
57:12And then there's the exact opposite approach,
57:14which is that IDH mutant pathophysiology
57:17conveys really a weakness that needs to
57:20be targeted and potentially promoted,
57:21which is really not just.
57:24To paraphrase simply Doctor Bender,
57:26thrust of work,
57:28and so this is actually.
57:30Pretty interested in potentially
57:32performing animal models where
57:33we can show them metabolic,
57:35correlate, Stew these interventions,
57:37but we have the potential also
57:39for doing so in the clinic,
57:41and that's really why I find the
57:44Warburg index as opposed to the pre
57:47clinical measures to be so exciting.
57:49This could be put in as an endpoint
57:51and potentially a phase two or
57:53phase three study very shortly,
57:55so hopefully over the next year
57:57I'll be able to recruit these
58:00cohorts and really have some
58:01exciting things to share.
58:03Great, well I look forward to it Zack.
58:06So it is the top of the hour and I
58:08want to be sensitive to everyone's
58:10time so I wanna thank Zack and
58:12Jason for really 2 outstanding
58:14and informative talks about novel
58:16approaches to imaging for the CNS.
58:18And of course thank all of you for
58:21joining us today and enjoy the
58:22rest of your day. Thank you.
58:26She.