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

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

May 17, 2022

Yale Cancer Center Grand Rounds | May 17, 2022

Presentations by: Dr. James Farrell and Dr. Vasili Vasiliou

ID
7849

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.