"Pancreatic Cancer Early Detection and Prevention -The sweet promise of family and pancreatic cysts” and "Alcohol and Cancer"

Transcript

• 00:00Good afternoon everyone. Welcome to
• 00:02the Yale Cancer Center grand rounds.
• 00:06Today we have two fantastic speakers both
• 00:08who are in the developmental therapeutics
• 00:11program of the Yale Cancer Center.
• 00:15And why don't we get started?
• 00:16I'm delighted to introduce
• 00:18Doctor James Farrell,
• 00:19who is a professor of medicine in
• 00:22the director of the Yale Center
• 00:24for Pancreatic Diseases.
• 00:25He's an internationally recognized,
• 00:27expert and pancreatic disease
• 00:29treatment and research,
• 00:30and is known for his development of
• 00:33personalized therapy approaches for
• 00:35pancreatic cancer and early detection
• 00:37biomarkers for pancreatic cancer.
• 00:39He received his medical medical
• 00:41degree from University College
• 00:43Dublin and completed internal
• 00:44medicine training at Johns Hopkins.
• 00:46And a gastroenterology fellowship
• 00:48at MGH and Harvard Medical School.
• 00:51He then completed advanced Therapeutic
• 00:54Endoscopy fellowship training at
• 00:56mass General and Brigham and Women's,
• 00:58in addition to his clinical
• 01:00practice and pancreatic disease
• 01:01and interventional endoscopy.
• 01:03His clinical research has focused on
• 01:05early detection of pancreatic cancer,
• 01:07including studying pancreatitis,
• 01:09high risk individuals and pancreatic cysts.
• 01:12His translational research includes the
• 01:15development of personalized therapy.
• 01:16Approaches for pancreatic cancer
• 01:18and the evaluation of biomarkers
• 01:20and pancreatic disease.
• 01:22Delighted to turn it over to you
• 01:24Doctor Farrell and look forward
• 01:26to hearing what you have to say.
• 01:28Thank you.
• 01:29Thanks everyone and good afternoon.
• 01:33Thanks for the invitation.
• 01:34So we're going to talk
• 01:35about pancreatic cancer,
• 01:36early detection prevention this morning.
• 01:39It really is going to be an overview
• 01:41in the time allotted and kind
• 01:43of emphasizing some of the work
• 01:44that we've been involved with.
• 01:46Disclosures.
• 01:48So when you think about pancreatic
• 01:50cancer in terms of overall incidence,
• 01:51it's actually low down in the list,
• 01:53and maybe sometimes doesn't get as
• 01:55much prominence as other cancers
• 01:57such as prostate or lung or colon.
• 01:59But when you look at cancer related deaths,
• 02:01it jumps up the list,
• 02:02and it's probably around the
• 02:04third or fourth most common
• 02:06cause of cancer related death.
• 02:08So in 2022,
• 02:09it's estimated there'll be about
• 02:1162,000 cases and just under 50,000
• 02:14deaths related to it and has long been
• 02:17predicted and certainly on its way by 2030,
• 02:20it's expected to be the second most
• 02:22common cause for cancer related death.
• 02:25It also needs to be emphasized.
• 02:27The fact that yes,
• 02:28there have been improvements
• 02:29in the management and treatment
• 02:31of pancreatic cancer,
• 02:32but really,
• 02:33they have fallen short,
• 02:34although progress still continues
• 02:35to be made and just emphasizing the
• 02:38need for a better and improved early
• 02:40detection for this particular disease.
• 02:42If we're hoping to improve
• 02:44the overall survival.
• 02:45Now,
• 02:46there has been tremendous progress in
• 02:48the world of understanding cancer,
• 02:50biology of pancreatic cancer.
• 02:52Along the bottom,
• 02:53here is a normal progression through
• 02:55low grade and high grade dysplasia
• 02:57or so called pen and lesions to
• 03:00invasive pancreatic ductal adenocarcinoma.
• 03:03It always typically starts with
• 03:05the activation of an oncogene,
• 03:07and then it's been several
• 03:09well known characterized tumor
• 03:11suppressor gene mutations,
• 03:12including P53 and SMAD 4.
• 03:16It's also worth noticing that related
• 03:18to this is another entity of the
• 03:20pancreas called Ipmn or introductive
• 03:23papillary mucinous neoplasm.
• 03:24It also goes through a similar sequence,
• 03:27resulting in an invasive neoplasm
• 03:29with similar mutations, such as in K.
• 03:31Ras, but also some unique ones.
• 03:33Which is Gina Genas uncle
• 03:36Gene observation activation,
• 03:38but it's very hard to talk about.
• 03:43Carcinoma without without talking
• 03:45about the other disease of ipmn.
• 03:49It's also worth making the
• 03:50point that this progression,
• 03:51we think from the initial K.
• 03:53Ras mutation to the time of
• 03:55let's say metastatic cancer,
• 03:57is probably of the region
• 03:59of of about 11 years or so.
• 04:02And so this number is debatable.
• 04:03But basically it's a long time for us
• 04:05to try and intervene and understand
• 04:07what's going on during this sequence.
• 04:10However, it's also worth noting
• 04:12that in its early stages and pre
• 04:15invasive stages with pannin,
• 04:16it typically can't be seen.
• 04:18Radiologically,
• 04:18when an early stage cancer does arise,
• 04:21this can be seen by radiologic imaging,
• 04:25but in the time required to go
• 04:27from an early stage, resectable,
• 04:29surgically manageable pancreatic cancer
• 04:31to an advanced metastatic stage can
• 04:34be as short as one to 1 1/2 years, and so.
• 04:37At that point,
• 04:38the clock does start ticking.
• 04:40And it brings up the issue of missed cancers,
• 04:43interval cancers,
• 04:44cancers that may be seen on imaging
• 04:47with more advanced uses of of imaging.
• 04:50Now there's no shortage of biomarker
• 04:53signatures for early pancreatic cancer.
• 04:55This is just a selection of of some of these,
• 04:58and they all have very promising
• 05:00operating characteristics or AUC.
• 05:04So in the top left is a salivary
• 05:06based 4 gene panel of RNA that we
• 05:08worked with again comparing non
• 05:10cancers to patients with cancers
• 05:12with a very respectable AUC of .97.
• 05:17Below is a work of Anoop Sharma.
• 05:20He said who Jim looking at?
• 05:22DNA methylation markers?
• 05:23And this is a particular 4 gene
• 05:26cell free DNA methylation panel,
• 05:28again with very respectable AU C curves.
• 05:32We've kind of come to the age in
• 05:332022 where we now have the beginning
• 05:36of commercially available panels,
• 05:38not just for cancer in general,
• 05:41so you have heard of GRAIL and
• 05:42you've heard of cancer seek,
• 05:43but now Innovia has an imray pan candy,
• 05:46which is an antibody panel
• 05:49specifically for pancreatic cancer,
• 05:51and in the studies to date at
• 05:53least shows very promising AUC's
• 05:56for the differentiation between
• 05:57early stage cancer and control.
• 05:59And in fact,
• 06:00this is being currently tested
• 06:01in a high risk.
• 06:02Population the Pantheon One study
• 06:04in which we're involved with
• 06:07results of which will be out soon.
• 06:09But the problem is yes,
• 06:10there are all these great
• 06:12biomarker signatures,
• 06:12but they're not being applied or can't
• 06:14be applied to the general population.
• 06:16And this has to do with an issue of
• 06:19mathematics and the 1.6 lifetime risk,
• 06:21and the low,
• 06:22relatively low prevalence
• 06:23of pancreatic cancer.
• 06:25What that means is that even with a
• 06:27very good sensitivity and specificity,
• 06:29whereas you have a very high
• 06:31negative predictive value,
• 06:32you have a very low
• 06:34positive predictive value.
• 06:36And even as you increase the
• 06:38sensitivity and specificity of these
• 06:40tests in the general population,
• 06:42the positive predictive value
• 06:43only gets as good as about 20%.
• 06:46And what that means is that most of
• 06:48the positive tests that you're going
• 06:50to see in the general population
• 06:51will turn out to be false positive tests,
• 06:54and this is one of the major
• 06:55reasons why we haven't.
• 06:57Unraveled general population
• 06:59screening currently.
• 07:00So as a result of that,
• 07:01we tend to focus on high risk groups
• 07:03and the three big high risk groups
• 07:05which are these enriched groups
• 07:07that increase the prevalence of the
• 07:09chances of developing pancreatic
• 07:10cancer include new onset diabetes.
• 07:13And I'm not going to go spend
• 07:14too much time on this today.
• 07:16Shiraz Shari,
• 07:16who's kind of a leader in this area, spoke.
• 07:18Very passionate about this subject.
• 07:20Here at Yale several weeks back,
• 07:22but diabetes interplays with everything
• 07:24that we talk about with pancreatic system,
• 07:26family history.
• 07:27The other two high risk groups.
• 07:30So what about
• 07:31pancreatic cysts?
• 07:32So pancreatic cysts, and specifically
• 07:34a type of cyst called an ipmn,
• 07:36are incredibly common findings,
• 07:38incidentally, found typically on
• 07:40CT scans or Mris of the abdomen.
• 07:44We use a variety of imaging
• 07:47features of these incidental cysts,
• 07:49such as high risk stigmata,
• 07:51are they associated with jaundice or amass.
• 07:53Is the pancreatic duct,
• 07:55for example dilated,
• 07:56are worrisome features?
• 07:57Is there a nodule?
• 07:58Is there an intermediate ductal
• 08:00dilation of the main pancreatic duct is
• 08:02assessed greater than 3 centimeters?
• 08:04Is there a change in caliber?
• 08:05Is a cyst getting rapidly bigger over time?
• 08:09So we use these imaging features to try
• 08:12and better understand what's the risk of?
• 08:14This particular IP man having cancer,
• 08:18and so we think that overall
• 08:20there's a 1% chance per year of
• 08:23these IP amends developing cancer,
• 08:25and when we look at the imaging,
• 08:27one of the first questions that we
• 08:29end up trying to sort out is should
• 08:31these patients undergo surgery and so
• 08:33we use a combination of the imaging.
• 08:35But even with our best imaging in 2022,
• 08:38it's likely that anywhere in the
• 08:40region of about 60% of patients are
• 08:43undergoing unnecessary surgery,
• 08:44meaning that we are resecting
• 08:46low grade dysplastic lesions,
• 08:48not the high grade dysplastic,
• 08:50not the invasive cancer patients
• 08:52that we're really trying to find.
• 08:54And so this kind of begs for an
• 08:56improvement in this particular area
• 08:58and one particular area has been in
• 09:00looking at the role of cyst fluid,
• 09:02and so we have the ability with
• 09:05endoscopic ultrasound to pass a
• 09:07camera down into the stomach and
• 09:09sample the fluid in these cysts.
• 09:11And this can be very helpful for
• 09:12making the diagnosis of the cyst.
• 09:14Like is it an ipmn or some other
• 09:16type of precancerous?
• 09:18But it also has the ability for
• 09:19us to look at, for example,
• 09:21methylation markers,
• 09:22and this is very promising 2 panel
• 09:24marker that has a very good high
• 09:27operating characteristics for separating
• 09:28out low grade dysplastic system
• 09:30which we don't want to operate on
• 09:33and high grade dysplastic and cancer cells.
• 09:35So expect to hear more in time about
• 09:37these particular markers and SIS fluid
• 09:39as well as other even protein based
• 09:41markers in this particular field.
• 09:45The other issue with pancreatic
• 09:47cysts relates to surveillance,
• 09:49and so as we get better at deciding which
• 09:52patients shouldn't undergo surgery,
• 09:54it'll become obvious to people that the
• 09:56vast majority of these patients with I PMN
• 09:59nothing really happens them dramatically.
• 10:01Over time, they might get
• 10:03a little bit bigger.
• 10:04They're duct might get a little bit bigger,
• 10:06but their chances of developing cancer
• 10:09requiring surgery is incredibly low,
• 10:11but we're obliged to follow them,
• 10:13especially younger patients,
• 10:14because we're telling them your cyst.
• 10:16As a risk of developing cancer.
• 10:18And in that, the field of surveillance
• 10:20has really become a very complex issue,
• 10:22primarily because there's a lot
• 10:24of cysts involved,
• 10:25so it's estimated at about 6 million
• 10:27people in the United States.
• 10:28At least have some form of pancreatic cyst,
• 10:31and it's brought up questions of
• 10:32when should we stop surveying
• 10:34patients that have pancreatic cysts?
• 10:36Is there an age?
• 10:37Are there Co morbidities that we
• 10:39should say outweigh the risk of cancer?
• 10:41Is there any way of tailoring or
• 10:43having kind of a frank discussion with
• 10:45patients to kind of educate them on
• 10:47who needs surveillance and who doesn't?
• 10:48And is there any progress we could
• 10:50make in the realm of understanding
• 10:53the biology of progression?
• 10:54So we know for a fact that says do
• 10:57change at some says do change over
• 10:59time and some cysts will change
• 11:02even after periods of stability.
• 11:04On the flip side,
• 11:05we also know that stability,
• 11:06especially for small cyst,
• 11:08is a good hallmark, or it's not great,
• 11:11but it's a good hallmark.
• 11:12Nonetheless,
• 11:13in a variety of guidelines that are
• 11:14out there to help us understand who
• 11:16we should be following who we should be,
• 11:18stopping surveillance on the American
• 11:21Gastroenterology Association has
• 11:23made the recommendation that after
• 11:25five years of CIS stability that
• 11:28you should stop surveillance and
• 11:29this actually has been quite a
• 11:31controversial recommendation.
• 11:34I could choda one of the physicians
• 11:36in our research group had the
• 11:38ability to look at about 18 studies
• 11:41with over 10,000 patients followed
• 11:43for almost 60,000 patient years.
• 11:45And I could look at in these studies
• 11:47that have now long term follow up for
• 11:49patients with otherwise low risk IP men.
• 11:51So patients that we would typically
• 11:53just be following and he was
• 11:55able to notice that yeah,
• 11:56after five years or so,
• 11:59the risks of them developing progression
• 12:02is probably around 3% per year and the
• 12:05risk of them developing a cancer or an
• 12:08advanced lesion is about 1% per year.
• 12:11And when he looked at the
• 12:13subgroup of patients,
• 12:14so patients who were stable for five years,
• 12:17so this would be the group that we
• 12:18would typically talk about stopping.
• 12:20There's still a .2% risk per year
• 12:23of developing cancer long-term out,
• 12:25so we don't think that there's enough
• 12:27evidence right now to really be
• 12:30talking about stopping surveillance.
• 12:31What we do know is that there are
• 12:33subgroups of patients who we should
• 12:35be probably having a more intelligent
• 12:37conversation with,
• 12:38and particularly patients who
• 12:40have significant comorbidities.
• 12:42We had the ability to look at.
• 12:47440 patients that we were
• 12:49actively surveying at Yale over a
• 12:51period of about 56 months or so,
• 12:53and in that group of patients,
• 12:5644 patients died,
• 12:57but the vast majority of deaths
• 13:00on follow-up were not related to
• 13:03pancreatic disease, and in fact,
• 13:05when we took a cut off of a
• 13:07comorbidity index of four.
• 13:09So an index that takes in
• 13:11cardiac renal pulmonary issues to
• 13:13determine long term comorbidity,
• 13:15a cutoff of four.
• 13:17It's very good at predicting
• 13:18long term comorbidities,
• 13:20not related to pancreatic cancer,
• 13:22and so now we're beginning to have
• 13:25these discussions with patients
• 13:26based on their overall prognosis,
• 13:28not just focusing specifically on
• 13:30the issue related to their pancreas.
• 13:34This very useful tool that's now available.
• 13:36We actually have it on our high risk website.
• 13:39The PCD website is a validated
• 13:43tool that was initiated and
• 13:46validated in both Dutch,
• 13:48Italian and several US sites for
• 13:50looking at both the five year and
• 13:52the three year and five year risk
• 13:54of developing worrisome features.
• 13:56A high risk of matter if you
• 13:58have a a low risk branch.
• 13:59Strict IP men so you you as a patient
• 14:01are able to go on to the website.
• 14:03You're able to put in.
• 14:04The size of your cyst,
• 14:05for example.
• 14:06There's some other parameters like
• 14:08smoking is your SIS multifocal,
• 14:10and it's able to give you a pictorial
• 14:12representation of your risk of the
• 14:14cyst developing into worrisome
• 14:15features and high risk matters,
• 14:16so this is very helpful in
• 14:19discussions with patients overall
• 14:20and ultimately we would like to
• 14:22get greater numbers to to be able
• 14:24to calculate individual risk of
• 14:26developing an advanced neoplasia.
• 14:30But I think a key issue is also
• 14:32trying to understand at a molecular
• 14:34level what makes some sense
• 14:35stable for periods of time.
• 14:37What makes certain IP amends
• 14:39decide that they want to take
• 14:41off after five years and develop
• 14:43into an invasive malignancy?
• 14:45And to this end there was a need to
• 14:47understand IP mensys progression more.
• 14:50To date,
• 14:50there have been some limited data
• 14:52and the use of organoids derive
• 14:54some surgical resection specimens
• 14:56so patients who have gone to
• 14:58the operating room and people
• 14:59have been able to develop ipmn
• 15:02organoids for additional study.
• 15:03We've taken a slightly different approach.
• 15:05We were actually interested in the
• 15:07groups of patients that were surveying,
• 15:08so patients who do not go for surgery
• 15:11and using again endoscopic ultrasound.
• 15:13We've been sampling the fluid
• 15:15from these pancreatic cysts and
• 15:17generating organoid structures.
• 15:18This is very preliminary data,
• 15:20and these are some of the images
• 15:22that we are identifying similar
• 15:24to what we would see in organoids.
• 15:27To date we have studied 9
• 15:30patients with presumed ipms.
• 15:31They're all growing,
• 15:33they're all growing exceptionally slow,
• 15:35but we've been able to
• 15:36passage some of them as well,
• 15:37so this is a an interesting
• 15:39development to allow us to study.
• 15:41I PM and progression to maybe
• 15:43tailor approaches for individuals,
• 15:45and maybe offer interventions such
• 15:47as chemoprevention, so stay tuned.
• 15:51Now the other large area within the risk
• 15:55or the high risk of pancreatic cancer
• 15:57is your hereditary susceptibility,
• 15:59or your inherited risk of developing
• 16:01cancer pancreatic cancer raw,
• 16:02but we think that maybe about 10% of
• 16:04all pancreatic cancers are at risk for
• 16:07developing cancer based on a family history,
• 16:10and there's a variety of guidelines that
• 16:12we've been involved with specifically
• 16:13the CAPS guidelines to help us
• 16:15understand who we should be surveying
• 16:17and who we shouldn't be surveying.
• 16:18And very Simply put,
• 16:20there's a high risk group that
• 16:22carries a very high lifetime risk
• 16:25of developing pancreatic cancer.
• 16:27It includes individuals with
• 16:29mutations and P-16 puts YAGERS,
• 16:31but also individuals who have
• 16:33a family history with three or
• 16:35four first degree relatives.
• 16:36So these people are at a higher risk
• 16:39without a known genetic abnormality.
• 16:41There's also a low to moderate risk that
• 16:43includes genes that you're familiar with,
• 16:44such as Braca one bracket,
• 16:46two other DNA repair genes
• 16:47like Paul V2 and ATM,
• 16:49but also again in there is a family
• 16:52risk of two first degree relatives
• 16:54and that carries a significant,
• 16:57albeit low risk than those that have
• 16:59three first three relatives with no
• 17:00abnormality identifiable in the germline.
• 17:04To take care of these
• 17:06individuals several years back,
• 17:07we set up a pancreatic cancer early
• 17:08detection clinic at Yale through smile
• 17:10through the general support of Smile and
• 17:12Javier Loras group and in this group.
• 17:14Currently we're following about 185 patients,
• 17:16most of them in protocol who are at high
• 17:19risk of developing pancreatic cancer,
• 17:21and again, you can see this from this group.
• 17:23The the majority of patients are actually
• 17:25individuals who have a strong family history
• 17:28but do not have any genetic abnormality.
• 17:30One of the original studies that was done
• 17:33in this area was that what's called the
• 17:35Caps three study and these patients are
• 17:37typically imaged with a variety of CT scans.
• 17:40Mris and endoscopic ultrasounds,
• 17:42and a small percentage of them will have an
• 17:45abnormality that requires surgical resection.
• 17:47So in Caps 3, for example,
• 17:50225 patients were enrolled.
• 17:52Umm?
• 17:54A total of 216 were ultimately
• 17:56studied and the majority of these
• 17:58are the time were familial patients.
• 18:00This is a multicenter study.
• 18:03For the majority of patients,
• 18:04no abnormality was identified,
• 18:05but you can see that for some of these
• 18:09patients had a dilated pancreatic duct.
• 18:11For example, a cyst, probably an ipmn,
• 18:14and a small percentage ended
• 18:16up having a solid lesion.
• 18:17In total,
• 18:18five of these patients
• 18:20underwent surgical resection,
• 18:212 of them had high grade dysplasia,
• 18:23and three of them had low
• 18:25grade dysplasia IP and then,
• 18:27although all five of them ended up
• 18:29with having either an intermediate
• 18:30or high grade dysplastic completion.
• 18:32In the form of a panel lesion.
• 18:35Very interesting data from these CAP studies.
• 18:37In fact has been the ability to
• 18:40collect pancreatic juice and what's
• 18:42been noticed in individuals who
• 18:45subsequently developed established
• 18:46pancreatic Dr Latner carcinoma is
• 18:48that investigators were able to go
• 18:50back and look at the pancreatic juice
• 18:52of these individuals at a time when
• 18:54they had no radiologic abnormality.
• 18:56And they were able to identify
• 18:59either combinations of P53 mutations
• 19:01or P60 mutations long before a
• 19:04radiologic abnormality was identified.
• 19:06So this is another direction to go in
• 19:09in terms of surveying these patients.
• 19:12The initial results of the Caps five study,
• 19:15which is a much larger multicenter study,
• 19:17which Yale was part have just been
• 19:20accepted for publication in in JCO in
• 19:23Caps 5 almost 1500 patients were studied.
• 19:28A total of nine screen detected
• 19:31pancreatic cancers were identified,
• 19:32of which eight were resectable
• 19:34and seven at a stage 1A,
• 19:37and when you put that together with some
• 19:39of the high grade dysplastic lesions,
• 19:41well over 50% of the patients
• 19:43enrolled in these studies had an
• 19:45achievement of what's called a
• 19:47successful goals surveillance.
• 19:48So we identified either an early stage
• 19:51cancer or a high grade dysplastic lesion.
• 19:54When all the patients from the
• 19:56caps one through five study
• 19:58were amalgamated together,
• 19:59what we were able to demonstrate was
• 20:02that those patients who were diagnosed
• 20:04during a surveillance protocol with
• 20:06pancreatic cancer had a much higher
• 20:09median survival than those that were
• 20:11diagnosed outside of surveillance protocol,
• 20:13showing some form of survival benefit
• 20:16within this within this initiative.
• 20:20Anca Chotto you know.
• 20:21Again, being very productive went and
• 20:23looked at some of these surveillance
• 20:25studies that were done more
• 20:27concerned about what was happening.
• 20:29Not so much when patients were
• 20:30initially enrolled, but as they
• 20:32were followed over a period of time.
• 20:34He took 13 of the most recent studies
• 20:37and what he noted was that in 53
• 20:39patients that were identified with
• 20:42pancreatic ductal adenocarcinoma.
• 20:43In these 13 odd studies or so.
• 20:46Whereas 22 patients or 41% had goals of
• 20:50surveillance achieved so in early cancer,
• 20:52a high grade dysplastic,
• 20:54a very worrisome,
• 20:55almost 60% of patients had an advanced Lee.
• 20:58A more advanced lesion including
• 21:01metastatic lesions.
• 21:02He tried to look at some of the
• 21:04factors that might be associated
• 21:05with these late stage presentations.
• 21:07It had nothing to do with
• 21:09surveillance modality,
• 21:10a baseline imaging abnormality,
• 21:11even the presence or absence of
• 21:13a germline mutation.
• 21:14A lot of the patients who presented
• 21:16were actually asymptomatic.
• 21:17We were able to look at the timing of
• 21:20preceding imaging and most patients
• 21:22had a normal preceding image.
• 21:24There was some questions about
• 21:26diagnostic errors in the in the limited
• 21:28data that was available and there was
• 21:29some issue of surveillance adherence.
• 21:31In some of this data.
• 21:34And what this leads into is kind
• 21:36of a growing conversation about
• 21:37how we can do better.
• 21:39You're going to see more and more
• 21:40of these types of studies in
• 21:42the next couple of years or so.
• 21:44This is the initial study that
• 21:45proved this point.
• 21:46These are patients who had a diagnosis
• 21:49of pancreatic ductil adenocarcinoma made,
• 21:52and when we when they went back
• 21:54over a year or so,
• 21:55it was said that the pancreatic
• 21:57cancer could be identified.
• 21:59So a variety of of methods were
• 22:03looked at in these individuals.
• 22:05But issue is with to do with issues
• 22:08relating to abnormalities that were
• 22:10identified on imaging that could
• 22:12be seen and maybe radiomics or some
• 22:15other feature could help figure that out.
• 22:17I think it's important to say,
• 22:18just to summarize,
• 22:20I'm sorry.
• 22:30That the the stage of pancreatic
• 22:32cancer at an early stage is improving,
• 22:35especially in younger populations,
• 22:37and the overall survival related
• 22:39to early stage pancreatic cancer is
• 22:42increased from about 44% in 2004.
• 22:45And now getting closer
• 22:47to about just over 80%.
• 22:49This is unclear why this is happening,
• 22:52but may be related to increased
• 22:54use of abdominal imaging,
• 22:55and perhaps some of the
• 22:56surveillance programs.
• 22:56So we're beginning to gather some
• 22:59information about the benefit of both
• 23:02the surveillance programs as well as.
• 23:04As well as.
• 23:06Are the outcomes related to
• 23:09those surveillance programs?
• 23:10And I'll leave you with this.
• 23:11Notice something to kind of
• 23:13look forward within the CAPS
• 23:14cohort of patients at Hopkins.
• 23:16Currently there is now open a mutant
• 23:19Karas targeted vaccine for patients at
• 23:21risk of developing pancreatic cancer.
• 23:23This is a phase one study that
• 23:26requires multiple intramuscular
• 23:27injections over a period of time.
• 23:29The initial outcome is for
• 23:31safety and tolerability,
• 23:33but they are going to look at changes in
• 23:36K Ras specific CD8 and CD4T cells at 2.
• 23:40And that four years.
• 23:42I'm also interested to know that modern
• 23:44it does have an M RNA based KRAS target.
• 23:46These are typically being
• 23:48used in in oncology trials,
• 23:50but may actually have a role
• 23:52in the high risk population to
• 23:54ultimately prevent and the the
• 23:57development of pancreatic cancer.
• 23:59So in summary,
• 24:00therefore just looking at the time.
• 24:03We currently are not performing
• 24:05screening in the general population.
• 24:07We are focusing on high risk groups,
• 24:09such as pancreatic cysts.
• 24:10Although we're trying to get
• 24:12better at surgical selection,
• 24:14but also get better at tailoring
• 24:16individuals who should be surveyed
• 24:17and those that should not be
• 24:19with respect to the familial
• 24:21pancreatic cancer cohort patients,
• 24:23we're getting better at documenting some of
• 24:25the outcomes associated with these studies.
• 24:27Really,
• 24:28with the view to improving
• 24:30those outcomes long term.
• 24:32And I think you'll hear more about nuance.
• 24:34Set diabetes.
• 24:35It certainly plays a role.
• 24:36And it it.
• 24:37It helps us stratify our
• 24:39patients with pancreatic cysts
• 24:40and familial pancreatic cancer.
• 24:42And I would use this talk just to say
• 24:44that there are plenty of opportunities
• 24:46within our group for collaboration,
• 24:48for additional biomarker developed
• 24:50development and validation,
• 24:51but also in the realm of imaging.
• 24:54And just to say that really it
• 24:56takes a group of people to try
• 24:57and keep these studies going.
• 24:58This is a picture of Ankit who's been
• 25:01incredibly productive and helpful.
• 25:02Getting our group up and running by there.
• 25:04Several other individuals such as
• 25:06Scott and disease and Ling helping
• 25:08on the the steady side as well as
• 25:10our really close and productive
• 25:12collaboration with Doctor,
• 25:14Hutch, and Doctor Sharma's lab.
• 25:15Thank you.
• 25:18Wonderful doctor Farrell.
• 25:19Thank you so much for
• 25:22that really nice overview.
• 25:24I don't see any questions in the chat,
• 25:26but if if there are those watching
• 25:27who have a question, please type it
• 25:30in and I'll make sure to ask it.
• 25:33I have a question for you,
• 25:34so it I'm thinking about the sort
• 25:36of the root cause of the increased
• 25:38incidence in pancreatic cancer.
• 25:40Because we we're seeing an
• 25:42increase incidence nationally,
• 25:43but also in the state of Connecticut,
• 25:45correct?
• 25:45And so it's either I can't remember
• 25:49what you said the the number of
• 25:52pancreatic says of the population
• 25:54that have pancreatic cysts.
• 25:55It was.
• 25:55It seemed like a quite large
• 25:57number, typically 6,000,000,
• 25:58is a number that's quoted.
• 25:59Yeah, if you would do extrapolation
• 26:01from imaging studies and extrapolate.
• 26:03Up to to the general population,
• 26:06so are we seeing an increase in the
• 26:09instance of cysts or is it diabetes and
• 26:13therefore with diabetes? Is it obesity?
• 26:15So what do you think is the root cause
• 26:18driving this increased incidence?
• 26:21There's different explanations given for
• 26:23the different increases specifically
• 26:25for pancreatic ductil adenocarcinoma.
• 26:28It's felt that it's also
• 26:29related to an aging population,
• 26:31so as the population ages,
• 26:32that's driving up the overall incidence
• 26:34of it, so that's one explanation,
• 26:36but for sure there are other issues
• 26:38with it and so issues related to.
• 26:43Like you know, metabolic explanations
• 26:44and obesity would be one one explanation.
• 26:47Trying to link that then to pancreatic cysts.
• 26:49The reason for the large volume of cysts
• 26:52are perception that there are more.
• 26:53This is really to just do
• 26:54with the use of imaging.
• 26:55So the prevalent use of MRI scans
• 26:58CT scans has really been driving
• 27:00why we see more assists.
• 27:02Also, imaging scans are getting
• 27:04better so we can see 3 millimeter,
• 27:05says 2 millimeter cysts on
• 27:07MRI scans done routinely.
• 27:09Now the question is.
• 27:10Can finding those cysts be converted
• 27:13to a better early detection strategy
• 27:15for ipms the OR for pancreatic cancer?
• 27:19The issue is that maybe those cysts
• 27:22account for 1015% of the total volume
• 27:25of pancreatic ductal adenocarcinoma.
• 27:29OK, thank you David.
• 27:30RIM had a question.
• 27:32Stage ones went from 40,
• 27:33some to 80 some percent.
• 27:35Survival is that due to greater
• 27:38diagnosis in stage one and have
• 27:40high stage diagnosis decreased.
• 27:44So this this phenomenon is from is from
• 27:47SEER data and all the positive glowing
• 27:50phenomena has been related to stage one a.
• 27:53So it has been the increase in incidence,
• 27:55the increase in survival associated
• 27:57with stage one as the decrease in age of
• 28:01diagnosis and it's not seen in the other.
• 28:04The other stages it's not even seen
• 28:06in stage twos and for sure it's not
• 28:09being seen and advanced stages.
• 28:10So there's something going on
• 28:12and so it's pure speculation.
• 28:14Whether it's related to the fact that people
• 28:16are more worried about pancreatic cysts,
• 28:18you know our surveillance programs
• 28:19in high risk individuals that
• 28:21count for certain population,
• 28:22but I'm not sure they account for
• 28:23all that population to switch it,
• 28:25so there's something going
• 28:26on that's changing,
• 28:27but it's it's a unique facet of stage one,
• 28:30as rather than the global
• 28:32numbers in in pancreatic cancer,
• 28:35and then with that year period of
• 28:38stage one progressing to metastatic,
• 28:40that's probably explaining in 2030 being the.
• 28:44Second, cancer mortality related
• 28:46to pancreatic cancer, correct?
• 28:49I think that's true,
• 28:50and I think also because there
• 28:51have been some significant
• 28:53improvements in other cancers, right?
• 28:54So you're seeing you know they're
• 28:56being slow improvements and having
• 28:57some improvements in the therapeutic
• 28:59side for pancreatic cancer.
• 29:00But you know, we really need to
• 29:02make a real dent for the early
• 29:04detection to really kind of begin
• 29:05to move that needle a bit better.
• 29:07And then the last question from
• 29:09Rosa is there also an increase of
• 29:11incidence in patients with young onset?
• 29:13And I believe you just.
• 29:15They said that in answering David's
• 29:17question, the age of the age of the
• 29:20diagnosis for the stage 1A's is going down,
• 29:23not for the other councils but for
• 29:25the other stages, but the stage one
• 29:27age of diagnosis has gone down.
• 29:29There are data about the overall decrease in
• 29:32the age of diagnosis of pancreatic cancer,
• 29:34and it may in fact be associated
• 29:36with slightly different types of
• 29:37genotypes and molecular profiling and
• 29:39some of that data has been kind of
• 29:41presented here at Yale in the past,
• 29:42so certainly focusing in
• 29:44on the younger population,
• 29:45hearing about a younger population.
• 29:47With pancreatic cancer,
• 29:48which is certainly very concerning.
• 29:50Well, thank you so much.
• 29:52It'd be great to to continue our
• 29:54our work here with the focus
• 29:56on Connecticut and how we can
• 29:58really improve upon the lower
• 30:00the incidence and or mortality.
• 30:02So thank you so much.
• 30:04Thanks very much.
• 30:06OK, if you can stop sharing and
• 30:08I'm now I'm delighted to introduce
• 30:11Doctor Bacillus Vessella who
• 30:13is chair of our Department of
• 30:15Environmental Health Sciences in
• 30:17the Yale School of Public Health.
• 30:19He's also the Susan Dwight Bliss
• 30:21professor of epidemiology and
• 30:22of ophthalmology and visual
• 30:24science and of the environment.
• 30:26He received his bachelors in Chemistry
• 30:28and PhD in biochemical pharmacology
• 30:30from the University of Ioannina
• 30:32in Greece and then he trained in
• 30:35gene environment interactions,
• 30:37molecular toxicology and pharmacogenetics
• 30:39at the Department of Environmental
• 30:42Health in the College of Medicine
• 30:44at University of Cincinnati.
• 30:46He's established an internationally
• 30:48recognized research program
• 30:50that's been continuously funded by
• 30:52NIH since 1997 and his research
• 30:55interests include the etiology.
• 30:57The molecular mechanisms of
• 30:58environmentally induced human
• 31:00disease such as liver disease,
• 31:02obesity and diabetes,
• 31:04cancer and neurogenic
• 31:05neurodegenerative diseases.
• 31:06His laboratory uses state of the
• 31:09art integrated approaches that
• 31:10include metabolomics, lipidomics,
• 31:12expoza, omics tissue imaging,
• 31:14mass spec,
• 31:15deep learning as well as human
• 31:17cohorts and genetically engineered
• 31:18mouse models and we are delighted
• 31:21to have him here today to talk
• 31:24specifically about alcohol and cancer.
• 31:27Thank you Vasilis.
• 31:28Thank you many days my microphone.
• 31:30Yes, my microphone is on.
• 31:32Thank you very much for your nice work
• 31:34and thanks also James for pointing
• 31:37out our T 32 who has helped on the
• 31:41studies before before I start mine I
• 31:44also want to address a little bit of
• 31:47the question of Melinda your question
• 31:49regarding the increasing density of
• 31:52cancer lately one of the things that
• 31:54I would like to point out is we have.
• 31:57Some increases in environmental exposures,
• 32:00especially for the perfluorinated compounds,
• 32:03namely PFAS, which may have
• 32:06contributed in all all kind of tumors.
• 32:09I wish we should have a round table another
• 32:12time to discuss about all these factors.
• 32:14So today what I'm going to talk to you
• 32:17about it is molecular mechanisms of
• 32:20alcohol and cancer, and so we have.
• 32:24We have edited 3 books on alcohol.
• 32:27You cancer and one special issue on
• 32:30chemical biological interactions which
• 32:33was based on my third international
• 32:37conference on alcohol and cancer,
• 32:39which we held it here in Newport.
• 32:42A couple of just before the COVID
• 32:46As a matter of fact,
• 32:47we just received a note from
• 32:51from Springer that our books doing so
• 32:54good and alcohol and cancer and they want
• 32:57us to write another one very much.
• 33:00But we will see. So I have all there
• 33:05is this association between alcohol
• 33:07and cancer and it's actually, you know,
• 33:11there is epidemiological evidence that
• 33:13is kind or is convincing that alcohol.
• 33:16Is associated with several
• 33:18cancers listed in here.
• 33:19Mouth fighting, slurring, esophagus,
• 33:22colon and breast for women and you
• 33:27know there is some more breast and
• 33:29liver based on IRC and there is a
• 33:32probable liver and colorectal for women.
• 33:35One of the things that I have not
• 33:37included in this presentation though
• 33:39and I have to say that as well they
• 33:42have been epidemiological studies which
• 33:44indicates that alcohol in sometimes.
• 33:47Is a positive factor in preventing alcohol,
• 33:51so I I don't have time to go with that.
• 33:56I'm gonna stick with the mechanisms today.
• 33:58Molecular mechanisms of the
• 34:00alcohol induced cancer.
• 34:02So let me before we go to that.
• 34:05And since we're talking about epidemiology
• 34:08is I want to tell you the categories of
• 34:12association between alcohol consumption and
• 34:14cancer and there is first case is sufficient.
• 34:17Evidence of a causal association,
• 34:19which is the case for every every study.
• 34:23There is sufficient
• 34:25evidence of an association.
• 34:27There is limited and suggestive
• 34:30evidence of unappreciation.
• 34:32Inadequate or insufficient to determine
• 34:35whether an association exists.
• 34:38Limited and suggestive.
• 34:40Evidence to of no association.
• 34:43This has been described very well in a
• 34:46paper by our junior faculty just walach.
• 34:51It was in in 2020 in the International
• 34:55Journal of Epidemiology,
• 34:57and this is worth reading it.
• 34:59One of the problems with alcohol.
• 35:02Based.
• 35:04Epidemiological studies is most of the
• 35:08studies are based on a questionnaire
• 35:10and rather than having clinical data
• 35:12in terms of the alcohol consumption
• 35:15and we know there are certain
• 35:17biases that could really interfere
• 35:19with the outcome of the studies,
• 35:21and this is most of the time
• 35:23people really are.
• 35:24You know, don't tell the truth.
• 35:26So answering the question,
• 35:27how many drinks you have there per week?
• 35:30Well maybe 1,
• 35:31maybe you know and could be just a bottle.
• 35:34Of of of of Hard Liquor per week.
• 35:38So this may create some problems,
• 35:40and this is what I'm trying to introduce.
• 35:43A new term which called the ALCOM,
• 35:45which is a panel of markets that could
• 35:48indicate what is your alcohol consumption
• 35:51throughout the years of your life.
• 35:53So in December 2020 I I was involved
• 35:59in an NCI workshop that we presented.
• 36:03You know the existing.
• 36:05Knowledge and everything.
• 36:06Evidence and gaps across the cancer
• 36:09continuum regarding the alcohol and cancer.
• 36:12So we have looked at from epidemiology to
• 36:16and biology of the alcohol and cancer risk.
• 36:20What needs to be addressed and how
• 36:23we can really work in preventing
• 36:26you know this alcohol consumption
• 36:29that could lead to cancer.
• 36:31Again,
• 36:32this is a readily available to everybody.
• 36:36And I'm going to go directly
• 36:38to the mechanism,
• 36:39so I've been working with alcohol metabolism
• 36:42since day one of my graduate studies,
• 36:45and that was the metabolism of alcohol,
• 36:48which actually is involved is been.
• 36:54Consider it as the mechanism of inducing
• 36:57cancer so your alcohol, your ethanol,
• 37:00is metabolized by alcohol dehydrogenases
• 37:02to an aldehyde which is a powerful.
• 37:05You know it's an aldehydes
• 37:07and an electrophile,
• 37:07which is capable of interacting with
• 37:10DNA and protein and forming adducts and,
• 37:14and this is a very important molecule in
• 37:18here, so ethanol can also be metabolized
• 37:21by catalase and also by cytochrome P.
• 37:24The 50s, mostly cytochrome P452 you
• 37:26want and to a lesser extent by 182.
• 37:30What happens during the ethanol metabolism.
• 37:33P4, fifties.
• 37:33You have generation of reactive
• 37:36oxygen species.
• 37:37You have glutathione depletion which
• 37:39leads to oxidative stress and as
• 37:41you will see later on we have the
• 37:44formation of further aldehydes namely
• 37:464 hydroxy nonenal and malondialdehyde
• 37:48which are further capable of
• 37:50causing DNA and protein adducts so.
• 37:54Ald H2 is the major enzyme
• 37:57which metabolizes acetaldehyde.
• 37:59The major product of ethanol,
• 38:01and it is converted to acetate and then
• 38:04from the acetate can go to kettle coenzyme,
• 38:07which can be used as a building
• 38:10biomolecule for a lot of.
• 38:13Cells, including the cancer cell,
• 38:16that's another story.
• 38:16We don't have the time to go over that today,
• 38:19so as you can see, the other heads and the
• 38:22reactive oxygen species are very important.
• 38:24My lab is focusing in all aldehyde metabolism
• 38:27and I'll show you a little bit more.
• 38:29But we also looking at the LDH
• 38:312 and a LDH 1V1 and a LDH 1A1.
• 38:35This is aldehyde dehydrogenase enzymes
• 38:37which they take us at aldehyde and
• 38:40convert it to acetate.
• 38:41So again you can see for the risk.
• 38:44Factors in terms of alcohol drinking
• 38:47as mentioned earlier there is aids,
• 38:50the personal history,
• 38:51family history, race and also diet,
• 38:54physical activity, obesity,
• 38:56smoking and alcohol use.
• 38:58As Melinda and James were mentioning above.
• 39:01So what Mike what we're doing in my lab
• 39:04is and I have a center funded by the NAA
• 39:06as we have all you can see here is this.
• 39:09The ethanol metabolism and
• 39:11also glutathione metabolism.
• 39:12They the synthesis of your major.
• 39:15Antioxidant of your system here and
• 39:18what you can see on those red letters.
• 39:21Are the enzymes involved in these
• 39:24pathways and we have single and
• 39:26double knockouts of all these enzymes
• 39:28which are involved in the eye in
• 39:31the ethanol metabolism and the
• 39:32interplay and essentially trying to
• 39:34clear up the reactive oxygen species
• 39:37generated and protecting yourselves.
• 39:39So we just published a review in cancers
• 39:43on molecular mechanisms of alcohol.
• 39:45And yours.
• 39:47Colorectal cancer so this is one
• 39:49of the area that my lab has been
• 39:52focusing for a number of years.
• 39:53We had EU one which I'm planning
• 39:56to go for the renewal as well and
• 39:59essentially again you can see that
• 40:02ethanol metabolism is involved in
• 40:04here and we have what I described
• 40:07you before the pathways here.
• 40:09But one of the things I want to tell
• 40:11you is the ethanol per se is not only
• 40:15metabolized by cytochrome P452 one,
• 40:18but.
• 40:18Constantly induces increases the
• 40:21levels of cytochrome P452E1 why?
• 40:24This is important?
• 40:25Because 2 E one it can metabolize
• 40:28the processing loggens into the
• 40:31carcinogens and that is very important
• 40:34and other area of the cytochrome P.
• 40:37For the two one it can increase
• 40:39the cell proliferation and also
• 40:41as we discussed it can create
• 40:43reactive boxes and species.
• 40:44The other is the important
• 40:46roles of both sides.
• 40:48From P452 you are and also you
• 40:50know the aldehyde dehydrogenases
• 40:52in retinoic acid homeostasis,
• 40:55which they been also involved
• 40:57in the the whole process.
• 40:59Another important issue here is
• 41:01the ratio between NADH and NAD
• 41:04which is completely changed based
• 41:07on the ethanol metabolism.
• 41:09Another area which ethanol could
• 41:11affect is the one carbon metabolism
• 41:14and that has effects on the DNA
• 41:17methylation which can really.
• 41:19Umm?
• 41:20Give a lot of.
• 41:24Changes in DNA methylation associated
• 41:26with cancer, as I told you before,
• 41:28I get there may can be used as macromolecule
• 41:32biosynthesis including including
• 41:34in the cancer cells we have a lot.
• 41:37I don't have the time to go,
• 41:39I just want to give you a brief
• 41:41overview of what's going on.
• 41:42So one of the major thing.
• 41:43So here if we can focus is you
• 41:46have the the adduct formation,
• 41:49the DNA and the proteins.
• 41:51I'm just going to show you
• 41:52some examples of the DNA.
• 41:53And we're gonna talk about
• 41:55some the inflammation as well,
• 41:58and we're gonna go from there.
• 42:00So what happened with the
• 42:02acetaldehyde and also the other
• 42:04aldehyde generating the DNA attacks?
• 42:06So these aldehydes are both in electrophiles,
• 42:09they can interact with
• 42:10bases of the DNA, and
• 42:11they can form others. And
• 42:13these adducts then they they are
• 42:15responsible for causing mutations
• 42:17into your into your transcripts.
• 42:20And I said aldehyde by.
• 42:23Also interact with various amounts.
• 42:25Can give a crotonaldehyde and
• 42:28this also conform further.
• 42:30Adducts in here at the same
• 42:32time as I mentioned before,
• 42:34you also have an increased lipid
• 42:37peroxidation from acetaldehyde,
• 42:38which is due to the glutathione depletion
• 42:41which generates further aldehydes for
• 42:44hydroxyzine on and all, and so on.
• 42:46So you have another type of the
• 42:48ethanol the the shock should
• 42:50go on Guana sitting here.
• 42:52Another type of attack.
• 42:53So it is very well documented that
• 42:56both acetaldehyde per se or the
• 42:59byproduct atheists that can interact
• 43:01with DNA that can cause addicts,
• 43:03and these others can lead to mutations
• 43:05and they can cause the cancer.
• 43:06This is a causative effect,
• 43:08and this is what helped to establish and put.
• 43:13That the goodbyes,
• 43:15as ethanol as a cancer agent.
• 43:19Another area I am not going to go
• 43:21on this aspects in here what I want
• 43:24to tell you is that ethanol also
• 43:26can induce inflammation and changes
• 43:28in the cytokines and chemokines
• 43:31and then they can have a various
• 43:33effects into all the signaling which
• 43:35essentially they can affect the DNA
• 43:37repair mechanisms into the system.
• 43:39So the importance this is less
• 43:42studied but this is an area that.
• 43:44We should emphasize and as a matter of fact,
• 43:48you know, this is what I'm going to tell you.
• 43:50What we're planning to do in here,
• 43:51but you know, again,
• 43:53it is a pathway that ethanol could
• 43:57affect all these pathways in here,
• 43:59including the DNA damage,
• 44:01and you know,
• 44:02and essentially having the more
• 44:04further mutations.
• 44:06So one of the
• 44:07areas that I am planning to expand
• 44:10is the immuno metabolism and
• 44:12this is the interplay between the
• 44:15monological and metabolic processes.
• 44:16And as a matter of fact we have
• 44:19published several papers on the role
• 44:22of glutathione in the control of
• 44:24the T cell and macrophage fashions.
• 44:26But essentially again you can see the
• 44:30mitochondrial metabolism here and how
• 44:32the ethanol metabolism can interfere
• 44:34with that in terms of the cancer.
• 44:37Incidents. As I told you before,
• 44:41the ethanol can also.
• 44:42I mean, alcohol can also affect the
• 44:45one carbon metabolism and ethanol
• 44:47can block the absorption of the
• 44:49folic acid and can interfere with
• 44:51all the the folate and cycle,
• 44:54and the methionine cycle which
• 44:56eventually and as you can see here
• 44:59in very stages through the either
• 45:02interacting with proteins and you
• 45:05know forming adducts or interacting
• 45:07with pathways or absorption or stuff.
• 45:10Essentially,
• 45:10we have a DNA hypermethylation which
• 45:12can be associated with cancer.
• 45:15And of course,
• 45:16you know that's the other pathway
• 45:18that you know by interfering
• 45:20with the one carbon metabolism,
• 45:22you can have decreased through the thione,
• 45:24which really you know gives
• 45:27rise to oxidative stress,
• 45:29which is a result of reactive
• 45:31oxygen species generated by the
• 45:34cytochrome P-450 metabolism of
• 45:36the P42 and taking a break here.
• 45:40What I wanted to tell you is,
• 45:42in the slide before here
• 45:44is the broker synonyms.
• 45:46We have a lot of Procter
• 45:48synonyms exposed in our lives,
• 45:50so if alcohol induces the
• 45:52site from P452 you want,
• 45:54then we have increased levels
• 45:55of the two you want.
• 45:57So I've been exposed to dimethyl nitrosamine,
• 46:00for example the nitrosamines or the P.
• 46:02Fashion everything.
• 46:03Then you can have a further activation
• 46:06of this carcinogens and you can
• 46:08have this generation of reactive.
• 46:10Which is in species and further mutation.
• 46:13I'm gonna end up very quick.
• 46:15I'm gonna talk. I'm not gonna spend
• 46:18my time you all know the incidence of
• 46:20the colon cancer and what is going on.
• 46:23But my lab has been focusing on the colon
• 46:26cancer and alcohol metabolism we have.
• 46:30We were the first to clone the
• 46:32secondary enzyme. If you remember,
• 46:34said aldehyde is metabolized
• 46:36to acetate by the aldehyde.
• 46:39Progenesis Ald. Stew is
• 46:41the major enzyme, but we did
• 46:43found we cloned this enzyme and
• 46:46mitochondrial enzyme which is very
• 46:49similar to a LH2 and we cloned it.
• 46:52We expressed it throughout the
• 46:54years we made beautiful antibodies.
• 46:56We made the cover pages of several
• 46:59journals and we found that
• 47:02first of all that metabolizes
• 47:03acetaldehyde with very high affinity,
• 47:05which is makes it as equal as a LD.
• 47:08It's too in terms of clearing.
• 47:11The acetaldehyde but also what we found
• 47:14out is this enzyme is also involved
• 47:17into the retinoic acid metabolism,
• 47:19which is very important.
• 47:21So one of the things in early
• 47:24we found out that aldh 1B1 is a
• 47:28potential biomarker for colon cancer,
• 47:30so we have screened several
• 47:32several panels of humors,
• 47:35and we found that especially
• 47:37for colon cancer,
• 47:38every single column cancer sample.
• 47:41But we have tested.
• 47:43It really expresses AL H1B1
• 47:46at the very high level, very
• 47:48high level and which we didn't see it
• 47:50in long breast on ovary or anything.
• 47:53And it was especially this it
• 47:55was not a LH1A1, it was a L
• 47:58H1B1 and this has to do also.
• 48:00You know with the colony
• 48:02formation and everything else.
• 48:03So we also in addition to colon cancer.
• 48:06We have also found out that
• 48:10ADH 1B1 plays a really big.
• 48:11Call in pancreatic cancer.
• 48:13Trying to make a connection
• 48:14with James talk earlier on,
• 48:17so this is the AL H1B1 and then you can
• 48:22series really high expression of this
• 48:24in the pancreatic Andrew carcinoma.
• 48:26So one of the things that actually
• 48:30you can use that as a prognostic
• 48:32market is you can take the tumor
• 48:34and then you can really isolate aldh
• 48:37positive and aldh negative sales,
• 48:40and then you can put them in culture.
• 48:42As you can see,
• 48:43if aldehyde hydrogenase is not present,
• 48:45you have very small formation
• 48:47of the colonies,
• 48:48but if they LDH positive you have
• 48:50really have seen the tumor formation.
• 48:53So for somehow this a LDH is involved
• 48:57in the tumor proliferation initiation.
• 48:59I don't know we're still looking at the
• 49:03role of this throughout either through the.
• 49:05DNA repair mechanisms,
• 49:07or through retinoic acid.
• 49:09It's an active area,
• 49:09so we have several papers on the
• 49:13how the Ald H1B1 could be that,
• 49:15and we found out that can be
• 49:18modulating the wind better.
• 49:20Catherine Pathway and the the also
• 49:24P1K they get signaling pathway,
• 49:27but the most important thing,
• 49:28and this is a work that we have
• 49:30done and we have identified that it
• 49:34is immunohistochemical market for.
• 49:36Further,
• 49:36for colorectal cancers and we look
• 49:39at that and several several samples
• 49:42and including some comparisons
• 49:44that we have done here at Yale.
• 49:47So it's a very strong market for that.
• 49:50And whereas as I said,
• 49:52we're still looking on what is going on.
• 49:55So one of the ways that we have trying
• 49:57to address the role of this is we
• 50:00have generated specific knockouts,
• 50:02so it's a tissue specific inducible knockout.
• 50:06The triple knockout mice show
• 50:07the APC mean mice.
• 50:09We know that the they are forming,
• 50:13they're
• 50:14forming many cancers.
• 50:15So anyway to make time is running
• 50:18we have generated a triple knockout
• 50:20of this with a PC and everything.
• 50:23So this mice we have found out that
• 50:26this is the ASPCA knockout and this
• 50:28is the well typed knockout mice
• 50:31and this is the experiment.
• 50:33This is how we generate it.
• 50:34It was a painful process.
• 50:36Triple knockout is not an easy way to do it,
• 50:39but the way that you're doing that
• 50:40is you have an industrial model,
• 50:42you you treat them with tamoxifen,
• 50:44you delete the gene and then you can
• 50:47further figure out of what's going on.
• 50:49So we did not find anything
• 50:52any difference in the.
• 50:54Vehicle treated mice and also in
• 50:57the tamoxifen treated groups at
• 50:59the numbers were not evident in
• 51:01jejunum or ileum in these mice.
• 51:03However, we did find the
• 51:06carcinoma colorectal adenomas,
• 51:08which in the knockout developed significant
• 51:11loan numbers of the macro and enormous.
• 51:15And there was a significant reduction in
• 51:18the total macroadenomas in the knockout.
• 51:20So, when we knockout the gene
• 51:22in a model that.
• 51:24Induces
• 51:27colorectal and the normas, uh it is the gene.
• 51:32If you knock out the aldehyde progenesis
• 51:34you reduce you can see that you reduce.
• 51:36So this confirms our initial studies
• 51:40that the ALDH 1B1 it is involved in the
• 51:44development of under cellular carcinomas.
• 51:48And we have been trying to to dissect
• 51:51more more involvement of this gene and we
• 51:54didn't see any difference at the P53 level.
• 51:58But we did see a decreased expression of
• 52:01the beta catenin in the knockout, a LH now
• 52:06beta catenin knockout for beta catenin.
• 52:11Expression which you know that Becca
• 52:13took Catenin is plays an important
• 52:15role in the development.
• 52:16All colon carcinoma.
• 52:19So the expression of of 191 could be used as
• 52:25a novel biomarker in identified colorectal
• 52:28cancers and also in pancreatic cancers.
• 52:31The Althe knocked down because
• 52:33the dramatic reduction of humor,
• 52:35growth, and loss of function of APC,
• 52:38and options of.
• 52:39Maybe it's trying to be 1 reduces the
• 52:42column adenoma and in turn delays
• 52:44that emerged in the progression
• 52:46of cancer in that to that effect.
• 52:49I have collaborated with.
• 52:53And cuts and we have developed
• 52:56special specific inhibitors of the
• 52:58aldehyde dehydrogenases that could
• 53:00be used for delaying the expression,
• 53:04delaying the progression of the
• 53:06tumor once it's been detected so.
• 53:11It looks like the Ald H1B1 is a
• 53:13key player in this carcinogenesis,
• 53:16so if I can go back a little bit on
• 53:19the molecular mechanisms to conclude my
• 53:22studies in here and the the directions
• 53:24is the alcohol metabolism is a key
• 53:27player through the cytochrome P-450,
• 53:29or through the aldehydes
• 53:31generated in here and then.
• 53:33You have also the changes in the
• 53:36NADH NADH ratio, which we can have
• 53:39also have epigenetic modifications.
• 53:41Remember reactive oxygen species.
• 53:43They can cause the inflammation
• 53:45that can lead to cancer.
• 53:46In addition to that,
• 53:47you also, as mentioned,
• 53:49this is very important here.
• 53:51This is especially with increased
• 53:53exposure to environmental casino egens
• 53:56the high levels of the two one they
• 53:59can lead to DNA damage segmentation.
• 54:01Then they can cause cancer.
• 54:03And of course you know the DNA repair
• 54:06can be also be affected by both the
• 54:08two U one and also the alcohol.
• 54:11Double so a very important process in here,
• 54:14and this is where we're focusing as well.
• 54:16Is how ethanol metabolism could the could.
• 54:21Have a defect in the day DNA
• 54:24repair as well and as I mentioned,
• 54:26also you know we have the one carbon
• 54:29metabolism and DNA methylation.
• 54:31I didn't have time to go on your micro
• 54:34RNA in here but also I did mention
• 54:37the crosstalk between these pathways.
• 54:39The alcohol and the immune system
• 54:41which eventually they can end up in
• 54:43causing epigenetic modifications
• 54:44that they can cause the cancer.
• 54:47This is a slide that the best
• 54:49slide that I've seen in terms of.
• 54:51Mark concluding all the effects of
• 54:55the alcohol in terms of the cancer,
• 54:57and this was from the former director
• 55:00of the metabolism of the NAIA SAMSARIC,
• 55:02who is a very good friend and
• 55:04colleague of mine,
• 55:05and I want to tell you this slide is I'm,
• 55:09you know, a little bit sad,
• 55:11but my next fifth international
• 55:13conference on alcohol and cancer
• 55:15was going to be in in Greece 2021.
• 55:18Unfortunately with the COVID we
• 55:20have to move it ahead and probably.
• 55:23It's not gonna be 2022.
• 55:25It's gonna be probably
• 55:272023 and I expect to see quite a few of our
• 55:31Yale colleagues here. Thank you,
• 55:34Melinda. I'm going to stop and
• 55:35get some time for questions. Thank
• 55:37you vicellous.
• 55:38Count me in on a trip to Greece.
• 55:41I know you just returned
• 55:43and I wasn't invited.
• 55:44Anyway to the topic at hand.
• 55:47I was intrigued at the beginning of
• 55:49your talk when you were talking about
• 55:51measurement error and the fact that often.
• 55:54We measure alcohol intake through
• 55:56questionnaire and we know there's
• 55:58a lot of misclassification with
• 56:00that underreporting, perhaps,
• 56:02and then that misclassification
• 56:06really attenuates the, say,
• 56:08the hazard ratio to the null.
• 56:10So in reality the impact of
• 56:12alcohol on cancer is probably
• 56:15even higher than noted in studies,
• 56:18but you then mentioned what
• 56:20do you call an alcohol zone
• 56:22or something of a channel of.
• 56:24Can you can you discuss that briefly?
• 56:26A little bit more So what
• 56:28we you see. Also show me this term
• 56:31similar to the Exposome and I'm
• 56:33trying to pattern actually this word,
• 56:36so I'm trying to figure out
• 56:38through animal studies and human
• 56:41studies how I can define a.
• 56:45Motif of changes that you can utilize
• 56:50by looking at the blood and finally
• 56:53modeling it to how much alcohol the one
• 56:57person has consumed during lifetime.
• 57:00This is not an easy task.
• 57:02OK, so because one of The thing is
• 57:05remember you can drink alcohol and then
• 57:08even if you measure a few of the enzymes,
• 57:11you're a pathic enzymes if you have.
• 57:13If you have abstinence of alcohol.
• 57:15Delivery cover so you don't know to
• 57:18how much alcohol you have drunk,
• 57:20So what we're trying to do is we're
• 57:23trying to have a a more educated.
• 57:28Measurement of determining how
• 57:30much alcohol a person have done
• 57:33throughout life and the same
• 57:36thing as the explosion concept.
• 57:38As I said, it's not easy,
• 57:39but we're trying to do that and
• 57:41we're trying to do with animal
• 57:42studies and also with human studies.
• 57:44This is one of the of the
• 57:46ways that it can help.
• 57:48Really, the epidemiology to assess you
• 57:51know the causal effects of alcohol because
• 57:53they this is another area of big debate.
• 57:56Melinda, as you know, you know,
• 57:57there was a couple of years ago
• 57:59there was one paper from New Zealand
• 58:01and it's saying all the women,
• 58:02even if they have one one drink.
• 58:05Per year they can develop colon,
• 58:08I mean breast cancer and if you look
• 58:10at really of these studies they were,
• 58:12you know,
• 58:13based everything on on on,
• 58:15on just the questioners.
• 58:17And as I said,
• 58:18this is not the accurate measure to do this.
• 58:23Yeah, yes, I agree.
• 58:24So much work to be done. Well.
• 58:27Thank you so much to both of
• 58:29our speakers today and if others
• 58:32who tuned in have questions,
• 58:34I'm sure you can reach out to both
• 58:37our speakers via email and hopefully
• 58:39there will be some collaborations.
• 58:41Initiated from today's talk. Thank you.
• 58:44Both have a great rest of the day.
• 58:46Thank you.