A Role of Radiofrequency Ablation in Benign and Malignant Thyroid Diseases and Towards Precision Treatment of Cancer: A Novel Oncogenic Mechanism Mediated by Piwi Proteins

October 26, 2020

Yale Cancer Center Grand Rounds | October 13, 2020

Grace Lee, MD, FACS and Haifan Lin, PhD

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00:00Search and we'll start with our first
00:03Speaker, Doctor Grace Lee Doctor Lee.
00:05As many of you may know is an assistant
00:08professor in endocrine surgery.
00:10She received her medical degree from the
00:13University of Oklahoma College of Medicine,
00:16did her her clinical training,
00:18residency in Research Fellowship
00:19at the Brigham and Women's
00:21Hospital at Harvard Medical School,
00:23and then did her fellowship in
00:25endocrine surgery at the male clinic.
00:28Before we were very fortunate,
00:30obviously, to recruit her here.
00:32TL Doctor Lee is is really an innovative
00:35expert and endocrine surgery and
00:37is looking at new ways to combat.
00:40Obviously thyroid, parathyroid,
00:41cancer among others,
00:42and seeing how we can, you know,
00:45leverage new techniques to
00:47improve the care patients,
00:48and I have a firmer understanding
00:50of the disease and Grace.
00:52I want to thank you for taking
00:55the time to join us for cancer,
00:58grand rounds and welcome hearing you talk.
01:03Thank you that confuse.
01:05That was very kind introduction.
01:08I am delighted to be able to
01:11present an area of my clinical
01:14interest with everyone.
01:19Share my screen.
01:25Works.
01:29Alright, so my name is Grace Lee.
01:32I am a new ish endocrine surgeon to Yale.
01:37I joined I was very fortunate
01:41to join Yale earlier this year.
01:44Sort of at the height of the
01:47pandemic from Tulane Medical Center,
01:50down in New Orleans and I have been an
01:54early adopter of this new technique,
01:58called Radiofrequency Ablation
01:59in thyroid at Tulane.
02:01So I just wanted to share my experience
02:05and what I know about where you
02:08frequency ablation so hopefully
02:10we can also start this treatment.
02:14At Yale as well. I have no disclosures.
02:21My talk will briefly touch
02:23on several different areas.
02:25I'll just touch on the
02:27background of how the RFA works.
02:30The physics and mechanism and brief history.
02:35Current procedural guidelines.
02:37When we are deploying something
02:41knew there are governing bodies who.
02:45Guide us as far as indications and when
02:48not to do it or concerned and will cover
02:52why we should be looking into this.
02:56What are the risks and the advantages
02:59and will also visit efficacy and safety
03:02of this technique as well as I'll
03:06show you a little video clip of how
03:09this is done and future directions.
03:14Super Cutaneous Ablation is a technique
03:17that obviates the need for a surgery an
03:21I'm sure many of you are familiar with.
03:25These needle often imaging guided.
03:29Way of eliminating undesirable
03:32tissue of their multiple different
03:35ways of burning or zapping things,
03:38we have utilized laser,
03:40microwave cryotherapy,
03:41freezing it, burning it,
03:43even injecting ethanol to a
03:46chemical esclerosis things,
03:48or Hifu which is high intensity
03:52focused ultrasound.
03:53Today we are going to focus
03:57on radiofrequency ablation,
03:58which is on the spectrum of these
04:02energy harnessing ablation techniques.
04:05Radiofrequency just a brief.
04:07Physics is concentrating heat or thermal
04:11energy at the tip of an electrode catheter.
04:15By alternating current and this
04:19frictional heat that gets generated
04:23from ionic molecules will.
04:26Turn into conductive heat from
04:28this frictional heat and create
04:31this Adelaide of unit.
04:33An if you sustain this heat
04:35enough in that area,
04:37this thermal energy will.
04:40Cause irreversible cellular damage,
04:42so essentially coagulations
04:44necrosis but without charring the
04:47tissue or carbonation of tissue.
04:51Radiofrequency Ablation in medicine.
04:52Interesting Lee has been utilized
04:54for a long time.
04:56It has been around in medicine for over
04:5975 years and some of the areas that.
05:03Have already started using
05:05regular frequency ablation.
05:07Are wide cardiology started using
05:10this for a rythmia vascular surgery?
05:13Surgeons use for varicose veins.
05:17Orthopedic surgeons an for us
05:20there uncle logic purposes for
05:22radiofrequency ablation that you may
05:25be familiar with for either meta,
05:29static or primary liver lesions
05:31in pulmonary Mets, Adrenal Mets,
05:34solitairy,
05:35renal lesions as well as Barrett's esophagus.
05:40History of thyroid RFA is not
05:43as deep as the history of RFA
05:47in other parts of the body.
05:502001 was kind of burst here.
05:53I am at year for thyroid RFA.
05:57The paper at the top for Catania's
06:01radio frequency evolution of the fire.
06:04Guided ultrasound is single animal report.
06:07The animal used was a pig. In Japan.
06:12And that this was just a proof of concept.
06:16Is radiofrequency ablation feasible?
06:18Is this safe?
06:19In subsequently.
06:20It's interesting that our colleagues at
06:24ground both Interventional radiology
06:26and surgery Department got together and
06:30try this RFA in recurrent thyroid tumors.
06:34So this technique has been utilized.
06:37Has been kind of played with
06:40for now nearly two decades.
06:44The person who actually took it
06:46and ran with it is this physician
06:49Interventional radiologist after Beck.
06:51Doctor Beck is located in
06:54Austin Medical Center in Seoul,
06:56Korea.
06:56He himself also had multiple benign
07:00thyroid nodules and about 25 years
07:03ago he was recommended by Korean
07:05surgeons to undergo a thyroid surgery
07:08an he did not want to surgery,
07:11so he started looking into what other ways?
07:14Are there to eliminate thyroid nodule
07:17and he started to focus on RFA.
07:20Not only he started doing this for.
07:23Patience.
07:24He himself has undergone this treatment
07:27so he has been really transparent
07:30about the results of RFA and he has
07:34been a passionate advocate for how this.
07:37Technique should be utilized an efficiently,
07:40safely and he has given multiple talks.
07:44He's been the most prolific.
07:47Writer in the RFA.
07:49Literature for this technique.
07:51So in 2009, the Korean Society of
07:54thyroid radiology came up with
07:57recommendations for how Virat RFA
08:00should be deployed and in 2012
08:03they came up with the 1st edition
08:06of guidelines for thyroid RFA.
08:08In 2017, they revised the guidelines
08:11and came up with a more updated
08:15version of thyroid RFA guidelines.
08:17Since then, this technique has been
08:20utilized worldwide in multiple
08:22hands-on teaching sessions,
08:24and workshops have been taught
08:27by Doctor Beck in others.
08:29So Japan, Taiwan.
08:31Obviously,
08:31a lot of Asian countries as
08:34well as European countries have
08:37embraced this technique,
08:39and it has slowly gotten to the US as well.
08:45So last year this is obviously pre
08:49kovid medical conference that we
08:51don't have anymore group picture
08:54folks from all over the world came
08:57together for this Korean Society of
09:00ultrasound in medicine conference case.
09:02Some insult and I was fortunate
09:05to participate in this conference
09:07in learn RFA from this conference
09:10as well as Doctor Beck afterwards.
09:14So there is a great interest and.
09:18The things that I have learned
09:20in the collaboration in the
09:22friendships that I have made.
09:25In Korea have been invaluable.
09:28And it really has helped me a lot
09:30in a deploying this technique at
09:33my prior institution at Tulane.
09:35So in 2015, Italian radiologists,
09:38an endocrinologist,
09:39came up with a consensus opinion
09:43an in the UK.
09:45They came together and consolidated
09:48recommendation in 2016 and 2017 in Australia.
09:52So what about us? What about the US?
09:56Why are we not widely adapting RFA?
10:00Why are we just now catching on?
10:04So.
10:05There are multiple reasons as to why
10:08the US sort of has lagged behind
10:12in adaptacion of this technique.
10:15It's not that clinicians in the
10:18US have not heard of it,
10:21it's just that we have been a
10:24little bit more cautious and.
10:27As of late,
10:29just in the past couple years there
10:32has been a booming interest in RFA
10:35technique by multiple societies
10:38who deal with thyroid pathology.
10:41An I'm sure that this RFA technique
10:44will be widely deployed and widely utilized,
10:48and I hope that yell will also start
10:53offering this treatment as well soon.
10:57So the.
10:58A Sentinel event that kind of
11:01took off the interest in the USI
11:05believe is this paper which came
11:08out of Mayo Clinic in 2018.
11:11The group here are comprised of
11:14endocrine endocrinologist who
11:16actually do their own.
11:17FN eisen utilizes ultrasound in
11:20clinic to assess thyroid nodules as well as.
11:24Prominent Interventional radiologists
11:27they have.
11:29Published this case series comprising
11:3314 patients over the years of
11:382013 and 2016 in their result.
11:42Really has been terrific.
11:45They achieve volume reduction by 45%.
11:50As early as eight months and Durably
11:54at couple years out in very safely,
11:57so I think this paper actually sort
12:00of put RFA on the map for the US,
12:04clinicians and audience.
12:05So since then,
12:07there has been many workshops
12:09and conferences,
12:10and as of late I have been getting.
12:15Presentation notices almost monthly,
12:17so why are we excited about RFA like?
12:21What are the advantages?
12:23So one advantage that I as
12:26a surgeon really appreciate,
12:29is that patients have.
12:32Lower anxiety about undergoing a per
12:35cutaneous minimally invasive treatment
12:37rather than undergoing a surgery.
12:40Most of my patients,
12:42unlike patients in Korea,
12:44are a little bit less concerned
12:47about the cosmetic outcome.
12:49The scar after surgery,
12:51but they are still very anxious
12:55about just the prospect of
12:57having to undergo a surgery so.
13:01I think this technique,
13:03if the patient qualifies for it,
13:06will be highly beneficial from
13:08reducing anxiety perspective,
13:09and obviously this is
13:11percutaneous needle poke.
13:13There won't be a long.
13:17Scarred that will be left behind.
13:19Of course,
13:20in thyroid treatment world there
13:23has been a couple of modalities
13:27where we're taking out thyroid
13:31through the armpit axilla incision
13:34through the mouth transoral.
13:38Method,
13:38but each one of those scarless or
13:42scar hiding surgeries come with
13:45either an increased cost of robot
13:49deployment or longer surgery,
13:52longer recovery, etc.
13:54So those are.
13:57They probably have a role in
14:01the world of Barry.
14:03Treatment,
14:04but they're still not as optimal
14:07if the patient is truly aiming for
14:10the best cosmetic cosmetic outcome,
14:13and it's a needle poke,
14:16minimally invasive.
14:17There is no hospital admission for some
14:21of the thyroid surgeries that we do,
14:24of course, are outpatient, but.
14:28There is still recovery involved
14:30after general anesthesia.
14:32There is pain involved.
14:34But with this for Catania's technique of RFA,
14:37there is no general anesthesia.
14:39There is only one institution
14:41in the US currently.
14:43Who's doing this RFA under
14:45general anesthesia in Korea?
14:47This RFA is actually done in a
14:51clinic setting with no Mac sedation
14:54just under local anesthesia.
14:56It's a relatively short procedure,
14:59obviously is volume of the thyroid
15:01nodule dependent bigger to nodule,
15:03longer to procedure,
15:05but it's a relatively short procedure.
15:07I would say anywhere from 10
15:10minutes to 30 minutes per nodule.
15:13And repeat ablation is a possibility,
15:16so you're not burning any
15:19bridges if the first go.
15:22Does not workout for the patient.
15:25No hyper para no hypothyroidism,
15:28which is remarkable because we are
15:31only ablating the nodule in preserving
15:34the normal parenchyma of the thyroid.
15:37Is virtually unheard of to
15:40get hypothyroidism after RFA.
15:42Treatment in also because
15:45it's nodule specific.
15:47There's no hypoparathyroidism either,
15:49so minimal complication risk.
15:51There could be voice changes
15:54and temporary discomfort,
15:56but compared to surgery I would say
16:01it's either equivalent or less and
16:05overall lower cost and that comes from.
16:10Not admitting the patient no
16:13prolonged or time or anesthesia,
16:16etc.
16:18So what are the downsides to RFA the risks?
16:22There are several.
16:25I just mentioned that repeat
16:27procedure is a possibility,
16:29but sometimes it's a necessity.
16:31So just one go around.
16:34It may not be enough to achieve
16:37therapeutic effect,
16:37so obviously having to do a repeat
16:40procedure is a risk an I would also
16:44say that is operator dependent.
16:46Many procedures are operator dependent
16:48surgeries or operator independent and
16:51that's why we advocate for.
16:55High volume Endocrine Surgeons to be doing
16:59endocrine procedures just the same with RFA.
17:02The more fast I'll the operator is
17:05with ultrasound and needle guidance,
17:08the better the outcome will be in.
17:11Some patients may not be able to
17:14tolerate a procedure without sedation,
17:17whether it's related to pain or anxiety is.
17:21Quite interesting to see them stoic nature
17:24of these Korean patients that I observed
17:27that Awesome Medical Center last year.
17:30I know that 18 gauge needle that's
17:33almost looking like a harpoon hurts,
17:35but they were very stoic.
17:37They said that they're not having any
17:40pain and they tolerate it just fine,
17:43but when I have been doing fine
17:46needle aspiration, thyroid nodule,
17:48biopsies in clinic setting although
17:50is 27 gauge needle much finer.
17:52Many of the patients complain of pain,
17:54so it will be interesting to see how
17:57many patients can actually tolerate this
17:59kind of a procedure without sedation.
18:02Complications when there is something
18:04being done to any part of the body.
18:07There could be associated complications.
18:09Overall rate is pretty smaller 2 to 3%,
18:12which is probably equivalent
18:14to a surgical treatment.
18:16There could be dis phonia which is
18:19about 1% in this data is coming.
18:22This data is coming from multi
18:24institutional pulled data so about
18:261% and none of it was permanent.
18:29It was all temporary resolved after.
18:322 three months hematoma.
18:34Thyroid is very vascular Schimborn.
18:37That's probably a little bit more prevalent
18:40in RFA setting rather than a surgery.
18:43There are a couple of lower incident
18:47complications such as tumor rupture,
18:49which is unheard of in surgery,
18:52hypothyroidism, Abscess,
18:53Anna couple of anecdotal not
18:55reported in this study.
18:57Complications such as tracheal injury
19:00and brachial plexus injury when a
19:03new technique is being deployed.
19:05In multiple people are just trying it out.
19:08I think that there will be wide.
19:13A variety of complications that may arise,
19:15as well as the outcome.
19:18So RFA in thyroid.
19:20There are guidelines and indications,
19:23and most of it is based on
19:262017 revised Korean guideline.
19:28So these are indications that
19:30most experts agree that we should
19:33be doing this for benign thyroid
19:36nodules causing compressive symptoms.
19:38If the patient has cosmetic concern
19:42and the nodule should be of size
19:46at least 2 centimeter or so.
19:48An if it's enlarging but has benign cytology,
19:52but.
19:53We have not set any definitive
19:56maximum thyroid nodule size for
19:58the treatment and Rica.
20:00Insist after failure of ethanol.
20:03Ablation of experts will agree that
20:06ethanol revelation is more studied,
20:09more tridan,
20:10better method for recurrent cyst or.
20:14Cyst of the thyroid treatment
20:17rather than rfa.
20:19Autonomously functioning thyroid nodule.
20:21This is toxic nodule indication.
20:24I personally have tried.
20:27Rfa in toxic nodule.
20:30It works beautifully and.
20:33That's sort of made me a believer
20:36of RFA technique.
20:37Entirety of nodule should be visible
20:40on ultrasound for safety concerns.
20:42It should not have any substernal
20:44component in.
20:45Nodule should be sufficiently away
20:47from the vital structures in the neck.
20:50As you all know,
20:52there are nerves and.
20:55Vital blood vessels in the neck and.
20:59Since the Heat can transmit,
21:02it is important that the structures are
21:06constantly being observed and monitored so.
21:10We don't cause any.
21:14Undesirable damages.
21:16RFA is most effective in solid nodules and
21:19if the nodule contains macro calcifications,
21:23the RFA will not be as effective.
21:26Ideal candidate.
21:27The pathologic criteria we want to.
21:30Be 100% sure that it is benign
21:33by either 2 repeated ultrasound
21:36guided F na's and in Korea.
21:39What they do is core needle biopsy.
21:43This is not universally practiced.
21:46Way of establishing benign
21:48status of the thyroid nodule.
21:51But core needle biopsy is an alternative
21:56to a fine needle aspiration and
21:58we want to make sure that there
22:01isn't any sonographic features or
22:04malignancy seen prior to deploying RFA.
22:07And again,
22:08we want to make sure that surrounding
22:11critical structures are away from harm.
22:14Or if a guidelines so multiple
22:18different countries are coming up with.
22:21Guiding this RFA treatment to be deployed.
22:25Obviously,
22:26Korean guideline is the most comprehensive
22:29Italians Australians aace American
22:32Association of clinical endocrinologists.
22:34We have a little bit of more conservative.
22:41Recommendations for RFA.
22:43So we are currently only recommending
22:46RFA to be used for benign thyroid
22:49nodules that are causing cosmetic
22:51or cosmetic concerns or symptoms and
22:54should be biopsy proven to be benign.
22:58Contraindications who cannot
23:00undergo this procedure.
23:02Pregnant females if the patient
23:04has contralateral vocal cord palsy
23:07if the nodule is not seen in its
23:10entire T but the patient has
23:13cardiac implanted cardiac device.
23:16We can switch over to bipolar mode
23:19instead of regular monopolar electrode
23:22or deploy it in shorter bursts in
23:26lower energy or if the patient has.
23:29Anticoagulation onboard is should be
23:31stopped prior to RFA the indeterminate
23:34thyroid nodule is a Gray area.
23:37There has been a study published
23:40in Europe but it's just a limited
23:43number of patients and the Efficacy
23:46and the long term outcome of.
23:49Doing Arefeen indeterminate
23:50thyroid nodule has not been
23:52quite established and malignancy.
23:54We are pushing a little bit of
23:57the boundary on this malignancy.
24:00A territory, so I'll discuss that briefly,
24:03since we are under the umbrella of
24:06Smilow Cancer Center, RFA and thyroid.
24:09When we are dealing with toxic Nodules,
24:12Orix beautifully.
24:14If we can achieve at least 50
24:17to 80% volume reduction of TSH
24:20normalizes an by 12 months.
24:22Most people are euthyroid, but again.
24:26If your desire is to achieve immediate
24:29reversal of thyrotoxicosis or hyperthyroidism
24:31than RFA is not the way to go.
24:35An it may take a one more
24:37than one ablation session.
24:40Depending on the size,
24:42and oftentimes these toxic nodules
24:44tend to be a little bit on the larger
24:48side greater than 4 centimeter,
24:50so in that case combination of
24:52RF NRA I can be entertained.
24:56Or large toxic goiters.
24:58This is how the electrode of rfa works, and.
25:05And how the picture shows you how fine it is.
25:10This is much finer than then liver
25:15RFA electrode an this just purely.
25:19Equipment optimization is what has taken
25:24the RFA deployment in thyroid lag behind.
25:30Compared to the liver world,
25:32so this electrode is internally cooled,
25:35is about 18 gauge.
25:37Big and seven centimeter in length.
25:40So if we're dealing with a.
25:43Very big patient that comes into play.
25:48So liver has deployment of times whereas.
25:55Rfa in thyroid. We are actually
25:59introducing the electrode and.
26:01Pulling it out,
26:03which is called a moving shot technique.
26:06To ablate units, these are
26:10circles of ablation zone inside.
26:14The thyroid nodule.
26:16And you see the triangle containing recurrent
26:19laryngeal nerve and esophagus below.
26:21So those are the vital structures
26:24that we want to be avoiding.
26:28This is a brief video of mixed
26:32thyroid nodule that is undergoing.
26:35Radiofrequency ablation you see from the S
26:40make side introduction of the electrode.
26:43We want to be able to see the entire
26:47length of the catheter an it is.
26:50Introduced and.
26:55Treated ablated from posterior.
26:59To anterior and.
27:05Inferior to superior,
27:07so we actually ablate the
27:11entire ellipsoid thyroid nodule.
27:14Follow up, we do serial ultrasound
27:16to make sure there is and there is
27:20an adequate resolution of whatever
27:23the pathology said is being treated.
27:26In there is a concern for regrowth
27:29and that is partially due to
27:32inadequate ablation at the periphery.
27:35So incomplete evolution of the
27:39thyroid nodule is being advocated.
27:42I'll touch briefly on the Barid
27:45malignancy and RFA currently in the US.
27:47Not many centers are doing
27:49RFA for thyroid malignancy,
27:51however it has been done in other
27:54countries and more and more folks are
27:56pushing the envelope especially in
27:58the world of Micropapillary Carcinoma
28:01which is less than one centimeter if
28:04the micro papillary thyroid carcinoma
28:06is intra fire Riddle and there is no
28:10clinical or ultrasound evidence of.
28:12Lymph nodes spread the current American
28:15Thyroid Association guidelines say
28:18that you can either observe it with
28:21active surveillance or have the patient
28:23undergo a thyroid lobectomy overtime.
28:26We have found that even the patients
28:29who undergo active surveillance,
28:31there is about 13% operation rates.
28:34So instead of.
28:36Having these patients undergo an operation,
28:40why not RFA so?
28:44Clinicians overseas have published
28:47their data on Micro PTC,
28:50and the data is knew and not.
28:55Has garnered wider.
28:58Adaptation just yet,
28:59but I think it is coming in
29:02recurrent thyroid cancer.
29:04As a surgeon, you know redo reop
29:07neck or cancer is a bear territory.
29:10So if we can safely treat patient with
29:13percutaneous method it will be fantastic.
29:16Indeterminate Nodules as I briefly mentioned.
29:18There is lack of data on whether
29:21we should be using this technique
29:23for Bethesda three and four,
29:26so currently not recommended and
29:28this is to be determined.
29:31Briefly, just wanted to show
29:33you a little graph of how five
29:36year followup of 84 low risk.
29:38Micro papillary thyroid carcinoma
29:41had achieved 100%.
29:44Regression over five years and
29:46this is just showing that there's
29:50no neoplastic change secondary to
29:53radiofrequency ablation of thyroid nodule.
29:57It's mostly just a spin.
30:00Ion cellular change.
30:01And because RFA does not alter the
30:04thyroid capsule or cause neoplastic change,
30:08it is.
30:09OK to redeploy RFA if needed or have
30:13the patient undergo a surgery if needed.
30:18So I'm going to just wrap up my talk
30:21by saying that RFA availability an
30:24indications will continue to evolve,
30:27and I think this is not a fad,
30:30but this is a treatment method that
30:33will probably stay and management
30:35decision really should involve
30:37multidisciplinary team of experts and
30:40include the patient in the decision making.
30:43And I think this technique,
30:45given that it's relatively new to the US.
30:49May involve specialists from the
30:53Interventional radiology surgery in
30:55endocrinology and multiple host of pathology,
30:58etc.
30:59It is fitting for us to be
31:03introducing this technique.
31:06As Smilow and I am a strong
31:09proponent of inviting the patient
31:12into making what is best for them,
31:16so it is important for us clinicians
31:19to not introduce our own clinician
31:22bias just because I'm a surgeon,
31:25I'm not going to advocate a surgery.
31:29Ann,
31:30this is not a technique that I
31:33currently subscribe to 100%,
31:34but I do believe that it has
31:37a role and I'll be.
31:40I'll do my best to be impartial and
31:44introduced this technique to Yale,
31:46so more research obviously is needed
31:50and we are actively doing project
31:53looking at our own institutional data.
31:57So I'm just going to wrap up by
31:59showing you this quote by Hippocrates,
32:01those diseases that medicines do
32:03not cure or cure by the knife,
32:06those that the knife does not
32:08cure or cure by fire,
32:09those that fire does not cure
32:12it must be incurable.
32:13But this.
32:16Philosopher also said first do no harm,
32:19so it is really a responsibility,
32:21and it's imperative that we
32:24deploy this technique safely.
32:26And I'll take any questions and
32:28thank you for your attention.
32:31Or Grace, thank you.
32:32That was a really terrific summary
32:34and it's really wonderful that you're
32:37bringing this technology and technique
32:39to bear for our patients at Yale.
32:41Just because we're running a little late.
32:43I'm gonna. I'm going to suggest that
32:46anyone has questions should probably
32:48reach out to grace directly and and turn
32:51now to our next speaker. And really,
32:53our next speaker needs no introduction.
32:55Doctor hyphen Lin Lin, as you know,
32:58is the Eugene Higgins Professor of
33:00cell biology, professor of genetics.
33:02Obstetrics, gynecology,
33:03and Reproductive Sciences and he is the
33:05director of the Yale Stem Cell Center.
33:08His work since joining Yellen 06
33:10to launch the center has really
33:12taken this center to national
33:15and international prominence,
33:16his own work focusing on self renewing
33:19mechanisms of stem cells is really informed
33:21cell biology and cancer in multiple ways,
33:24and I think he's going to share
33:27with us the work that he's done in
33:30terms of a gene family that.
33:32He and his lab have discovered
33:34and its relevance to cancer,
33:35so hyphen thank you very
33:37much for speaking today.
33:39Well, thank you much Charlie
33:40for a very kind introduction.
33:42I'm delighted to have this opportunity
33:44to give a progress report on my own to my
33:48own colleagues and your Cancer Center.
33:50Although I've worked for many years
33:52on stem cells and developmental
33:54biology regarding Cancer Research,
33:56I'm completed a new kid on the block.
33:59So in the past few years or research
34:02on gene regulation or stem cells,
34:04let us to the cancer field.
34:06So today, instead of talking about
34:08my usual type of stem cell research,
34:11I'm actually going to share with
34:14you some preliminary results
34:15of our recent cancer work.
34:17And this actually is my first
34:19time talking about these results.
34:21I hope to get your expert input
34:24advice and potential collaboration.
34:26So to begin, let me share my.
34:31Slice
34:36screen sharing.
34:43OK can you see my slides?
34:45Yes OK, great wonderful yeah.
34:48So you know as Charlie mentioned.
34:51I will first give a bit background
34:54about some of our earlier work to
34:57pave the way for my cancer results.
35:01So in 2000.
35:041998 we discovered the Argonauts gene
35:07family as the first in family that's
35:10highly conserved during evolution.
35:13For its stem cell function and this Infirmary
35:16encodes a highly conserved group of proteins,
35:21called argument proteins that
35:23contains 4 functional domains,
35:25among them the PhD domain.
35:27Mydomain mines too small Agnes whereas
35:31period of mine actually resembles SH.
35:34And this gene or protein family
35:37has been subdivided into two
35:39subfamilies and you probably know
35:41very well about Argonaut subfamily.
35:44Which plays a central role in
35:46the micro angle and the angle
35:48iron mechanism and these proteins
35:51directly bind to sin is micro honest,
35:54which are in general 21 nucleotides long.
35:58And Becausw are gonna suffer.
35:59My proteins are expressed in
36:01most type of sales.
36:02That's why I mean I mechanism and
36:05microrna regulation works for all of us
36:07who are doing this type of experiments.
36:10However,
36:10I said stem cell person I was more
36:13interested in the other sub family.
36:15The piece of family cause it's
36:17mostly expressed in the German in
36:20the most primitive stem cells.
36:22So in 2006 my lap and almost simultaneously
36:26three other labs discovered that the
36:29piwi subfamily proteins bind to yet
36:32another class of non small coding,
36:35honest that we named Piwi
36:38interacting organisms.
36:39Or paying it for short so paying
36:42is just like PV proteins.
36:44They're mostly expressing that you're mine,
36:46and they're somewhat longer
36:48than Micro RNAs or Sir is.
36:51So in this slide,
36:52just just wanna share with you
36:54some salient features of Python
36:56is versus Micron is,
36:58which are better known in
36:59addition to being a bit longer,
37:02pang is a very complex,
37:03so in my lab we they have cloned
37:06over 16 Millions of these pioneers,
37:09which is in sharp contrast to
37:11the 1000 species or Micron is
37:13that's known in any Organism.
37:15And in addition, the pairing is target.
37:18All type of Genomic sequences,
37:21again in sharp contrast to microarrays,
37:23which mostly target the three point
37:26you TR or mature Messenger RNA is.
37:30And finally,
37:31the Biogenesis is very different.
37:33Hanges are mostly produced from
37:35long single stranded RNA's in
37:36conscious to Micro Arnie's feature.
37:39From here penari precursors.
37:42So this discovery is very interesting
37:44to us because as you all know
37:47that the molecule biology field
37:48relies on very important principle
37:51called the central dogma.
37:53Which tells us that genetic
37:55information in DNA is transcribed
37:57into Messenger RNA's and then
37:59further translated into proteins.
38:01And that's how life process starts.
38:04The discovery of Micro Arnesen small
38:07Angus like S Ion is further enriched
38:10this dogma by telling us that now
38:13there are two new mechanisms regulating
38:16the stability or the translational
38:19efficiency of micro earnings.
38:21However,
38:22when we looked into where these genes
38:25encoding pioneers reside in the genome,
38:27it to our big surprise they do not reside
38:31in this known gene coding region which
38:34only represents 1 to 2% of a genome.
38:38Instead, they mostly result in this
38:41junk DNA we call useful junk represent
38:44the vast majority of what you know.
38:47And it is those genes they produce
38:51these enormous number of Pioneers.
38:54So we were you following about
38:57this discovery, because if you
38:58likens our genome as the world,
39:00then the traditional jeans
39:02are like the Old World, The.
39:05Asia, Europe, continent.
39:06And somehow our research let us lend
39:10it to assure of a computer New World.
39:13We spy on agents now many other genes.
39:16So this actually was a pie I baked for my
39:20lab to celebrate the discovery of honey,
39:24and it's my first breaking product.
39:26And also this discovery was
39:28selected by science as one of
39:31the 10 breakthroughs in 2006.
39:33The only biology breakthrough
39:35that was selected.
39:37So, this excitement aside,
39:39the key question really is.
39:42Does any of these peyronies
39:44have any functions?
39:45So in past several years my lap is in
39:48focusing on these pioneers functions.
39:51It turns out these pioneers
39:53and their partner PV proteins.
39:55They can be present sometimes in the
39:58nucleus and sometimes in the cytoplasm.
40:00So we wanted to 1st know when these
40:04peripatric complexes in the nucleus.
40:05What's their function?
40:08To address the question,
40:10I'd like to bring your attention
40:12to a field called epigenetics.
40:14You probably know that epigenetic is
40:17a very exciting field that started
40:19gene regulation and the focus or
40:21current epigenetic studies focus on
40:24identifying epigenetic factors and
40:26illustrating how they modify the
40:28histone ordinate modification status.
40:29Therefore,
40:30turning on and off the expression of genes.
40:34However, to me this epigenetic
40:36factors there are so called down molecules.
40:39They mostly don't bind DNA,
40:41let alone recognize specific DNA sequences,
40:44but somehow they had to be guided
40:47precisely to specific genes in the genome.
40:49For example here,
40:51but not here or here.
40:53In order for epigenetic programming to work,
40:55and for the life process to unfold.
40:59So to me ascential question in genetics
41:01is what are the mechanisms inside the
41:04nucleus that can guide these enzymes to
41:07the right sites in the genome at the
41:09right time in the right type of cells?
41:13When we started our work a few
41:16epigenetic factors were illustrated
41:17to be guided by a few transcriptional
41:21factors to the promoters of a few genes.
41:24And that was exciting by small an exception.
41:27Becausw for soil represents
41:29a feedback mechanism,
41:30and Secondly,
41:31it was only accountable for very
41:34small number of genes in Arduino.
41:36So the big question to me existed and
41:39still in a way exist is that what's the
41:42mechanism that guides these epigenetic
41:45factors to their target sites?
41:47So,
41:48Fast forward to today after
41:50several years old research,
41:51we discovered that the PV panel
41:54complex it should play a central role,
41:56at least in the June sales to guide the
42:00epigenetic factors to their target sites.
42:03So this is how it works.
42:05So the peewee protein and its partner
42:07apparently will form a complex.
42:09And this complex will bind to Genomic
42:13sequences with complementary sequences.
42:15Actually, by binding to Nathan RNA
42:19That's tethered still to the genome.
42:23This then leads to the
42:25recruitment of this complex.
42:27Two other epigenetic factors,
42:29such as histone here to competent protein,
42:33one to this site,
42:35which initiated a bit genetic programming
42:37and this complex will further recruit
42:40other epigenetic factors such as
42:43Houston Metro transfers to the site,
42:46which further then further
42:48elaborate epigenetic programming
42:49by methylate in this case,
42:51Houston H3K9 Residue.
42:53So this is what we initially
42:56discovered into software and now
42:59in human and mammalian systems we
43:02found that this complex can also
43:05recruit DNA methods to the target
43:08size to achieve demethylation.
43:11So I'm happy to report that you know,
43:14up to now epigenetics study allowed
43:16us to discover a major mechanism
43:18in the germline cells that will
43:20recruit epigenetic factors.
43:22Too many sites in the genome to
43:25achieve epigenetic programming.
43:26And as you all know,
43:28such programming is very important
43:30for stem cell self renewal for
43:33German development for transposon
43:35silencing and so on.
43:37So then you might wonder
43:39what's the function of this P.
43:41We empowering molecules when
43:43they're in the cytoplasm.
43:45So again,
43:46just to briefly review what we
43:48found in the past few years,
43:50we found that they actually play a
43:53very important role in mediating the
43:56regulation of transposons and pseudo genes.
43:59Thoards protein coding genes.
44:01You all know that transposons
44:04are viewed as selfish parasites.
44:07That invaded our genome and
44:09traditionally and still today.
44:11Many textbooks regarding.
44:14Self is the element without any
44:16active function except for potential
44:18advantage during evolution.
44:20Pseudogenes are viewed as the
44:22default caucus of our active genes
44:24on their way out during evolution,
44:27but we found that transposons,
44:29pseudogenes actually play a very
44:31important role in regulating the
44:33regular protein coding genes
44:35that we know very well,
44:37and this regulation actually is
44:39mediated by the preparing complex.
44:41So, back to the central dogma, again, DNA.
44:44For protein coding,
44:46gene is transcribed into a pre
44:48Messenger RNA which is then.
44:50Kept tailed and the entrance prized
44:53become a mature Messenger RNA.
44:55It got exported into the cytoplasm.
44:59About two years ago,
45:00we discovered that about 50%
45:02of genes in human genome.
45:04It should contain transposon
45:06sequences in the three point beauty,
45:08our or their Messenger on is.
45:11That was very surprising finding to us
45:14and after that we found that actually,
45:17transposons actually actually
45:18expressed a low level,
45:20at least in germ cells and primitive
45:22and some primitive stem cells,
45:25and the transposon expressed transcript
45:27will be processed into mature.
45:29Long is and bound by peewee proteins too.
45:33From this peripera complexes.
45:35These complexes can then,
45:38as you can imagine,
45:40beautifully target their corresponding
45:42or complementary transposon sequences.
45:44That's hiding in the three point
45:47beauty of material Messenger
45:49is to regulate the expression
45:51of this Messenger RNA.
45:53In addition, we found that the so called
45:55the so called that you know pseudogenes,
45:57that that copies of our active
45:59genes are actually not quite dead.
46:01They also have a very important role.
46:03They are often expressed into
46:05Messenger on is in antisense,
46:08and those antisense Messenger honest
46:10will be processed by TV proteins.
46:13To become pioneers again and
46:15form complex with PV protein.
46:17And as you can imagine,
46:19this antisense RNA will be very
46:22capable or targeting the cognitive
46:24active genes of the sudo gene.
46:27So now we know the gene regulation actually
46:29is not a linear way like what's stated
46:32by central dogma is very complicated,
46:34and Pironi Imperial proteins
46:36play essential role there.
46:38Likewise, if you are aware of new discoveries
46:41on some other non coding on is such as long,
46:45noncoding,
46:45honest or called Lincoln for short,
46:48even the expression of these thousands
46:51of Lincoln is regulated by Python is.
46:54And this regulation
46:56originates from transposons.
46:57Because we found that many linkon is
47:00again content transporting sequences.
47:03So these sequences,
47:04like Trojans horse inside their
47:07enemies and the transposon.
47:10Derived piony,
47:11we're together with people holding
47:13bind to these target armies and
47:15regulate this target armies.
47:17So, just to summarize this part of my
47:20talk as a background for the cancer site.
47:23Again, if you like his argeneau as the world,
47:27then the traditional jeans that
47:29we studied most of the time.
47:32About 23 thousand of them apart of
47:34the small world at the Old World,
47:37and even in the Old World we often
47:40forget the presence of pseudogenes.
47:43In human there are over 14,000 pseudogenes,
47:46and the transposons over a million,
47:49so transposons.
47:50And apparently work.
47:51Let us landed ashore of a new world.
47:54Now the New World also contained
47:56another big class of non coding
47:59on is called Inca armies.
48:00Implying is actually serve a very important
48:03function to connect these two words.
48:06I've shown you very quickly in the
48:08Schematic Summary Paris can regulate
48:10the expression of traditional jeans.
48:13Panic and regulate expression of
48:15Lincoln engines powering it can
48:17regulate the expression of traditional
48:19jeans through information from
48:21transposon and even pseudo genes.
48:23Can you spy on its pathway to regulate the
48:27expression of the cognat active genes?
48:30So now for this audience you might
48:33be very curious about does any of
48:35these basic discoveries have anything
48:37to do with the clinical side?
48:40We reasoned that because all these jeans
48:42are so important for stem cell division,
48:45if you delete any of these genes,
48:47stem cell with differential
48:48into ordinary cell,
48:49we wondered if we overexpress
48:51these jeans wear that cause
48:53malignant professional stem cells.
48:55And will there be possibly A cause of cancer?
48:58So the question we really ask is is
49:00preparing a function related to cancer.
49:03So a number of years ago we took
49:06some human seminoma cancer patients.
49:10Their testicular samples versus
49:12testicular samples from normal males
49:15and other kinds of testicular cancers
49:18derived from non stem cell based malignancy.
49:21And we found that a human gene that
49:25we named he means human pee wee is
49:30just the overexpressed in seminoma.
49:33Which is known to be a stem
49:35cell derived testicular cancer.
49:37This in fact was the first thing to show such
49:40a high correlation to this type of cancer,
49:44so encouraged by that in the past few years,
49:47we decided to look into other forms of
49:50cancer to see if any of these P regions
49:53are over expressed in these cancers and
49:56we first took M at the breast cancer,
49:59especially triple negative breast cancer.
50:00For reasons you all know.
50:02And we first screened through six most
50:05representative lines of human breast cancer,
50:08and this is the normal human breasts tissue.
50:12And this is the mouse one.
50:15And we looked for the expression of peewee
50:18proteins or genes in this cancer tissues.
50:22There are four human genes
50:24encoding period proteins.
50:25They're called peewee like 123 and four.
50:29And we found out all four
50:32overexpressed and especially IPV 4.
50:34In all six breast cancer cell
50:37lines before becomes detectable,
50:39expressed and in five out of 6 lines period.
50:424 become expressed at least 50 times
50:46higher than what's in the normal tissue.
50:49So encouraged by this cell line based study,
50:53we decided to approach patients
50:56directly and we randomly sampled 20
50:59breast cancer patients for the appeal
51:01wise tissue between the Nonmalignant
51:04was tissue versus their own molecular
51:07breast tissue and to our delight,
51:09we saw that 10 out of 20 patients
51:13indeed showed version overexpression
51:16of the provisions.
51:18And to further confirm this correlation
51:20we went to NCI database and two screens
51:24through over 1000 cancer patients whose
51:26period expression pattern was known.
51:29And indeed we found that for those cancer
51:32patients with higher level or PV four
51:36expression there much worse prognosis.
51:38So based on this very solid correlation,
51:41then we wanted to know what's
51:43the role of PV 4IN.
51:44Breast cancer.
51:45Is this just a passive consequence of cancer
51:48development or it could be an active role in
51:51promoting cancer formation and development?
51:53So in that, to address the question,
51:56we first did the cell based experiment.
51:59This you probably a very familiar is the
52:02triple negative breast cancer cell line.
52:05Highly aggressive.
52:06When we did the wound healing assay.
52:09Normally if you remove this part of the
52:12breast cancer cells just within 36 hours,
52:15the residual cells will highly proliferate,
52:18highly proliferative and migrate into
52:20the central region to see all the void.
52:24However, if you just need to knock
52:27down the expression of P V4, then.
52:29For long time,
52:31much beyond actually 36 hours,
52:33these cancer cells fail to proliferate
52:35at high speed and they fail to migrate.
52:38And we've,
52:39you know,
52:40confirm this asset by chance
52:42will essay also indicate that
52:44PVL for knockdown affects cancer
52:47cell proliferation and migration?
52:49Then we wondered through what kind
52:52of molecular mechanism period 4
52:54achieve such a amazing function.
52:57And it turns out TV four is very important.
53:01In promoting the epithelial tamanika,
53:04more transition of this breast cancer cells.
53:08Because when we reduce the PV four expression
53:10in this triple negative cancer cells.
53:13Actually, that alone can revert
53:15this cell fate for mesenchyme all
53:18state back to epithelial state.
53:20So Soon as example here,
53:22ecad hearing is a typical epithelial
53:25marker and incoherent is Amazon Co
53:28marker and this is a loading control.
53:31The regular,
53:32a triple negative breast cancer cells
53:34are competing between carmalized.
53:36This express very high level,
53:39incoherent, but no expressional.
53:41Equal hearing is detectable now if
53:44we just knock down PV L4 to 70% or
53:47be higher efficiency and the three
53:50independent markdown conditions.
53:52Desales, I guess you know,
53:53revert back to the procedure failed.
53:56So that was very exciting to us
53:57because very few in the cancer
53:59literature as you know better than me,
54:01people can see that kind of Revolution.
54:03Then we say,
54:04why is peewee so important in controlling
54:07the wholesale faith transformation?
54:09And we looked into the molecular
54:11pathway to not pee wee.
54:13Four promotes the TGF beta and FDF data
54:16signaling pathways in cancer cells.
54:18So these signaling pathways are all
54:20highly expressed in breast cancer cells.
54:23But you knock down peewee expression.
54:25The expression is just a compromised.
54:29In addition to this,
54:30we were surprised to find that three or
54:34four also inhibit the expression of MHC
54:37two complex components in cancer cells.
54:40So this analysis allowed us to
54:43propose a model that actually PL-4
54:46is a very assume key regulator
54:49that promotes breast cancer.
54:51Uncle Genesis,
54:52it does so by promoting these typical
54:55and Progenics signaling pathways.
54:58Activities within promotes
55:00the cancer cell survival,
55:02increase their proliferation and.
55:04Cause them to have EMT.
55:07Meanwhile,
55:08the pee wee molecule will suppress
55:10the host immune system surveillance
55:13allow these cancer cells to
55:15escape the immune surveillance.
55:17So this was the first somatic
55:20and major cancer type that we
55:22looked encouraged by that.
55:23We wondered whether any other piwi protein
55:26expression is correlated and possibly
55:28A cause of other major type of cancers.
55:31Then we looked into a second
55:33major type of somatic cancers,
55:35namely gastric cancers.
55:37And here, as you can see,
55:39you probably are very
55:40familiar with this Histology.
55:42In the.
55:43Left panel this is just a chemical
55:46standing with another PV protein
55:49called PV L1 now standing Brown.
55:52You see,
55:53in this adenocarcinoma sections
55:55from either the gastric body or the
55:58gastric cardia or the gastric trap.
56:01And in turn regions.
56:03There are robust overexpression of PL-1.
56:07And in chronic gastritis,
56:09which is a milder form pre cancer condition,
56:12you see also a topic expression of PDL one,
56:16but at much lower level.
56:18P1L1 expression is not there
56:21in the normal gastric tissues.
56:23When we quantify that this expression
56:26level is nicely correlates to the
56:29advancement of the gastric cancer
56:31stages from stage one to four,
56:33you see increased expression of
56:35period one and also nicely correlate
56:38with the distant metastatic
56:39ability of these cancer cells.
56:42For you know not to not to
56:45multiple distant, not you see.
56:47Again these cells show higher level
56:49PV one expression and Interestingly
56:52its expression level is inversely
56:55correlated to the Differentiation State
56:57of these cancer tissues or cells.
57:00So based on that, we decided that
57:03the PO1 must likely also play a role
57:06in promoting gastric cancer and two.
57:09A test that question in also in
57:12addition to the cell biology and cell
57:16based assets as I showed you earlier,
57:19we also did the cancelled
57:22Genographic transform essay.
57:23So when we transplant these gastric
57:26cancer cells into nude mice.
57:29It growth, robust tumors,
57:31and if you introduce the
57:33negative control for knockdown,
57:35it does not affect tumor growth.
57:37However, if you introduce S Ioni,
57:40the specific knockdown,
57:42the expression of P V1.
57:44In this cancer tissues,
57:46you just reduce the tumor formation
57:49and when you looked into these
57:52two more tissue sections by,
57:54for example,
57:55the cell proliferation markers such as PCA,
57:58that's indicating Brown here or Ki 67
58:01you see in the wild type situation.
58:06The cells are highly mitotic and prolific.
58:09In the controller down you don't
58:12see any big difference.
58:14But in the period one knockdown
58:16you greatly reduced.
58:18The proliferation of these cells and
58:20that's a duplicate sure is the same thing.
58:24So based on that?
58:26You know we wanted to know.
58:29Weather Pang is appeared role in this period.
58:32Proteins function in cancers.
58:34We expected to see pioneers and
58:36cancer specific powers to show up,
58:38but to our surprise,
58:39when we did deep sequencing for the
58:42small non coding RNA population,
58:44we could not detect any pianese we detected
58:47lots of micro honest which is normally
58:49a smaller population than pioneers.
58:52But now even with this big presence
58:55of microrna population we cannot see
58:57any or if any just very few pennies.
59:01That's where a matching to the high
59:03level of heavy protein expression
59:05and let us too.
59:06Conclude or to hypothesize that
59:09piwi proteins function in cancer
59:12might be independent of Pianese.
59:15To really demonstrate that's the case,
59:18we generated this mutant PV proteins
59:20by mutating three of its residue
59:23in the PV domain that you might
59:26remember from my introductory slides.
59:29That's possessing the only cleavage
59:32activity and pioneer binding activity so.
59:35When you mutate these three residues,
59:37the resulting engineered mutant
59:39protein can no longer bind to pioneer.
59:41Then we wanted to see if this.
59:44Pilot Binding Deficient Mutant Perior
59:47one proteins are still oncogenic
59:49and turn out that's the case.
59:51So normally in these gastric cancer cells,
59:55if you do transfer your essay
59:58for their migratory ability.
01:00:00Highly migratory.
01:00:01Now if you knock down the P1 is question,
01:00:07you greatly reduced its migratory ability.
01:00:11But if you in this knockdown cell
01:00:13now reintroduce into these cells,
01:00:15that mutant PV protein that
01:00:16cannot bind to pay on it,
01:00:18but that's alone is sufficient.
01:00:21To restore the majority
01:00:22ability of these cells,
01:00:24so this analysis tells us
01:00:26that this pee wee function
01:00:28in gastric cancer,
01:00:29at least in gastric cancer,
01:00:32is actually very independent.
01:00:34So our latest results showed that
01:00:37pee wee actually in gastric cancer
01:00:39they do not interact with piramis,
01:00:42but they interact with the nonsense mediated
01:00:46decay immediate regulatory mechanism.
01:00:48An empty to regulate the cancer genome
01:00:51or cancer transcript on what we think
01:00:54what's happening is that the piwi protein,
01:00:57when it's highly expressed
01:00:59in these cancer cells.
01:01:01It directly target tumor suppressor cells,
01:01:03army and degree design is so that
01:01:05allowed the uncle genic alarm is
01:01:08to promote her ankle Genesis.
01:01:10And Meanwhile as you know,
01:01:12some tumor suppressor anger is
01:01:13themselves with directly supports.
01:01:15Cancer grows in the squashing function is
01:01:18not knock down because of PV overexpression.
01:01:21So we're very excited
01:01:23about these discoveries.
01:01:24In fact,
01:01:25this discovery started from to
01:01:27Safra and now we can always see the
01:01:30hope of approaching clinical site.
01:01:33Of course,
01:01:33I wanted to know whether you know
01:01:36we can use this as a therapeutic
01:01:39target and we have some preliminary
01:01:41results show that's quite possible.
01:01:44So shown here is a new method
01:01:47that's being developed in my lab.
01:01:50Is nanoparticles loaded with?
01:01:51This song is against these proteins.
01:01:54In this case,
01:01:55it's against another under binding
01:01:57protein called familiar that we
01:01:59also worked on and has also has a
01:02:01tumor function promoting function.
01:02:03You can inject these.
01:02:06Nanoparticles through Kelvin into
01:02:08the mice that contains human cancer.
01:02:11In this case, colorectal cancer graph.
01:02:15And 28 days after that.
01:02:18After they closed due to the injection
01:02:20and after four times or injection
01:02:23then you use city to visualize
01:02:25the tumor growth and the web micro
01:02:27angle is and sin is localized.
01:02:29So we label this as an every
01:02:32sci-fi and tumor with luciferase,
01:02:35so by city image Ng just 4024
01:02:37hours after the first injection.
01:02:40You can see these nanoparticles become
01:02:43highly enriched in the tumor cells.
01:02:46And then if you let these mice continue
01:02:49to grow and you can see normally.
01:02:53If you just in the ceiling
01:02:55control or randomize this,
01:02:57I only control this grafted tumor tissue.
01:03:00Grow quite robust in this new mice and
01:03:03also will start to undergo metastasis.
01:03:06See other spots within 28 days.
01:03:09But if you do tell,
01:03:11then injection of these nanoparticles
01:03:14loaded with anti this particular
01:03:16proteins are as I only you can
01:03:18really control the tumor growth.
01:03:20So you know,
01:03:22we really feel like basic research
01:03:24allows us to potentially found the
01:03:27computer novel oncogenic mechanism.
01:03:28That's not specific to a particular
01:03:31type of cancer,
01:03:32but probably is to multiple type of cancers.
01:03:36Through our own data,
01:03:38we've shown that in breast cancer,
01:03:40in gastric cancer.
01:03:42In seminoma and in prostate cancer.
01:03:44In skin cancer,
01:03:46in liver cancer and in colorectal cancer.
01:03:49At least subtypes of these cancers.
01:03:52They have high level of period
01:03:54overexpression and period appeared to be
01:03:57a driving mechanism for this type of cancers.
01:03:59So my stream is to use these
01:04:02TV proteins as target.
01:04:04To treat cancer,
01:04:05to develop new treatment for cancer becausw
01:04:08PV proteins. As I mentioned earlier,
01:04:10there only needed in the germline
01:04:13and come to adult states.
01:04:14They only needed in the male germ
01:04:17line because female germline,
01:04:19namely over does not have stem cells.
01:04:22Only spermatogonia stem cells active here.
01:04:24So basically you can completely
01:04:26knockout these proteins.
01:04:27The normal self development
01:04:29will not be affected.
01:04:30We've done so now called
01:04:32entire period family in mice,
01:04:34mice happily surviving.
01:04:35The only problem is the male
01:04:38mice and we predict them.
01:04:39Male patient in human,
01:04:41they will temporary loss fertility but
01:04:44that easily can be solved by stores
01:04:46and sperm right before the treatment.
01:04:49So this is my dream and I hope you
01:04:52know with potential collaboration
01:04:54with all of you in the future
01:04:57or some of you we can take,
01:05:00you know steps forwards and hopefully
01:05:03there will be a 2 new cancer.
01:05:06Treatment message will emerge from this,
01:05:08so I'd like to thank my lab
01:05:11members who did work and since
01:05:13I'm running over our stuff here.
01:05:17Hyphen that was fabulous body of work.
01:05:19And congratulations on all of it.
01:05:22And really, as you point out,
01:05:24it really does Availa bold new
01:05:27approach of cancer therapy.
01:05:28I know we're essentially out of time,
01:05:31but let me just ask one question beyond
01:05:35potentially targeting through SI RNA,
01:05:37are there other potential
01:05:38approaches to target these genes
01:05:40in terms of future Therapeutics?
01:05:42No, that's
01:05:43a very good question into it.
01:05:46The answer is yes.
01:05:47Because these proteins,
01:05:49not the atomic structure,
01:05:50have been resolved, so we know exactly
01:05:53how the active side looks like.
01:05:56And so we're also starting to
01:05:58use a small molecule based
01:06:01screen to find these mimics.
01:06:03Of this active site binding substrate,
01:06:05and hopefully those will be specific to
01:06:08target and knock down these molecules
01:06:10too well. That's exciting,
01:06:11and it sounds like a potentially
01:06:14new area for Therapeutics.
01:06:15Well, I know we're out of time.
01:06:18I want to thank those who joined
01:06:20us and thank hyphen and Grace
01:06:22for two really superb talks.
01:06:24Great work and thank you everyone
01:06:27and enjoy the rest of your day.
01:06:29Well, thank
01:06:30you very much for your
01:06:32invitation. Bye bye bye bye.