Best Cure For Prostate Cancer

i would like to tell you a bit about the work,some of the work, we are trying to do, which is trying to improveimaging of prostate cancer, and i’ll try to explain why. so, i just need to tell you i have some sharesin a company that is working out through one of the patentsthat i did, but it is not relevant to this, but i am obligedto tell people, by law. so this is the man’s journey through prostatecancer. i don’t know if there is a mouse i coulduse. did the arrow come up?

no, never mind. i’ll just explain. on the left hand side you can see that diagnosisoccurs, but probably by the stage that diagnosis occurs men have maybe had the disease for five toten years already. and then the choices seem to be either watchfulwaiting these days, it used to be surgery or radiation, but ifyou have a low gleason score, and probably all of you know what a gleasonscore is. it’s a grading of the cancer and there aretwo bits that they look at, they just say the bit that’s the worst andthe bit that’s, i mean sorry,

the bit that’s the most common has a gradefrom one to five and the next bit that’s the next most commonhas a grade from one to five, and they add those two numbers together tomake a gleason score. so, if your gleason score is six, it’s nowconsidered to be pretty mild, and you might be advised to go on watchfulwaiting rather than having an operation. but, if it’s seven or above, then usuallythe choices are that you should do something actively aboutit, like and operation or having radiation.

so, most men, after that, get better. but some men then, after a few years, findthat they have a rising psa. that’s the blood test for prostate specificantigen. and the reason that it’s so useful it’s now not being used so much for diagnosis, but it’s incredibly useful once you knowa man has prostate cancer, because it goes up and down with the volumeof the cancer, usually. there are some cases where that does not happen, but as a general generalisation it does.

and so the treatment for that is some kindof androgen ablation, or androgen therapy, which blocks the productionof testosterone. in the olden days they used to castrate men. that’s not done so much now. they use drugs instead to achieve that result. but the reason that the psa goes down is thatit’s actually driven by androgen, so the male hormone drives the productionof psa. psa is an enzyme, which is found in the ejaculate, and its role is to break down the little clotthat forms in the ejaculate,

which is called semenogelin, so that the sperm can swim out and do whatthey need to do. so it also makes fluids in the prostate. so psa is controlled by androgen. so, if you monitor the psa levels, its giving you an idea of what’s happeningwith the androgen. and it turns out that prostate cancer is verymuch androgen dependent and androgen driven. so, initially, the chinese eunuchs who usedto look after the harems were all castrated,

and they, none of them, ever developed prostatecancer. so, if you didn’t want to develop prostatecancer, you could become a nice boy soprano and singup high for the rest of your life. but that isn’t of course what happens. but it was one of the ways in which it wasfound that the androgen was so important. so, when that goes back up the androgen ablation usually brings the psadown again in many patients, but there are some who then go on to haveanother rise in prostate cancer. so by this stage, on this end of the graph,

we’re now talking about more advanced disease. the beginning one was sort of early disease,but a proportion of men get advanced disease. and when we are working in research, as iam, you tend to concentrate on this end because the surgery and the radiation canwork very well for many men at the early stage. so, we are trying to work out how we can savemen who have developed advanced stage cancer. so that’s why i’m talking about that endof the spectrum. so, if you’re newly diagnosed i don’twant you to think that, you know, i’m telling you, a song of doom about yourlife expectancy, because i’m not.

i’m trying to tell you about how we mighttreat and do things for men with late stage so when that goes up, as you can see by thatbrown line, initially the cancer is called androgen dependentor androgen sensitive. it becomes hormone refractory, because it now does not seem to need the hormone anymore, or castrate resistant. and at that time, or even a bit before it,it starts to spread and it spreads to other organs and in particularit goes to the bones. so bony metastases, they’re secondary depositsof cancer in the bone, are very common in late stage prostate cancer.

so, now what’s happened. ok. so this is just to explain what goes on inthe late stage cancer. you can still treat late stage cancer, whichnow don’t seem to be hormone dependent, with some new drugs that have been discovered. and what’s happening is the prostate canceractually makes its own androgen. so after you’ve taken away the androgen,by using androgen ablative therapies, it actually starts to make its own. it’s very clever.

i’ve always said the prostate’s the secondbrain, but people don’t like that answer. but they do, and, there are several mechanismsby which this can happen. first of all, it uses a back door pathway, which is not the normal pathway of metabolismfor making the androgen, in order to make androgen in the prostate. and the androgen binds to a receptor on thecell, which is on the surface of the cell. i mean, it binds, it carries it inside ofthe cell to the nucleus of the cell where it turns on a whole lot of genes. and another mechanism of getting over theneed for androgen

is that you get hypersensitivity of the androgenreceptor itself, so that it can bind other hormones as wellas testosterone. it can bind progesterone and oestrogen andother kinds of corticosteroids, so it does not need the androgen in orderto perform its work. or you can get mutations in that androgenreceptor, or you can have multiple copies of the androgenreceptor. so that if the level of testosterone is extremelylow it can still be reactive. so the drugs have to be designed to work toovercome these kinds of mechanisms that the prostate cancer produces.

this shows that backdoor pathway, so don’tworry about that. but if you can understand those mechanisms,then you can actually design new therapies. so that’s what this slide is really tellingyou. that’s my take home message. now i’m coming back to this one again, because what happens is that we really desperatelyneed imaging to tell us “do you really have a bad prostate cancer?” “do you have a cancer that isn’t too bad,even though the gleason score mightn’t say so?”

but should we be using surveillance? that means that you monitor the psa everysix months and maybe do some more imaging in a year’stime. should you be doing that, or should you begoing on to surgery or radiation? we need to be able to make those decisionsbetter, and if we could image the cancer and clearlysee the cancer there, we could do that with much more precisionand give better advice to men as to what sort of treatment might be goodfor them. and similarly, if we’re using treatments,

these are just new treatments that have comeup in the last five years. i mean a few years ago we did not have anytreatments for late stage cancer. now there’s a whole series of drugs. some of them are chemotherapy, so docetaxeland cabazitaxel. there is sipuleucel-t. it is an immune type of therapy that inhibitsthe prostate cancer from growing. and the abiraterone and enzalutamide are aimedat attacking the androgen receptor and the testosterone. and the 223 radium is a radioactive substance,

which also delivers a sort of high level ofradiotherapy locally. so, we need it to know, not only for diagnosing,but for treating. a lot of these treatments work in some menand not other men. and they have quite nasty side effects insome men and not other men. so if you’re unfortunate and have a badresponse and get very sick with having, say, docetaxel, we need to know is it working sothat we can stop it a bit sooner, or should we keep going and putting peoplethrough these nasty side effects who aren’t going to respond. but if we could image the cancer well we couldtell a bit earlier whether that’s working,

and that would help with the management ofthe disease. so, i’ve just put up here - and i don’texpect you to read it – it’s a great pile of clinical trials thatare going with all these new drugs. so it’s just to show you that and awfullot is now happening world-wide with all these drugs. and clinical trials are usually randomised, so a patient will be given one treatment ornot a treatment, so that you can actually compare what wouldhappen to them over time. and if the clinical trials aren’t done inthat manner,

then you can’t really draw appropriate conclusionsabout how good the treatment is. but this is just to show you there’s allthese trials and, in addition, whilst i showed you a whole series of drugsthat were there, we don’t know if we should combine the drugs. and if we should combine the drugs, or treatwith one then another, what order should we give those drugs in. because sometimes if you combine them they’rebetter, sometimes if you combine them it make it worse. and sometimes if you give one first you can’tuse another one.

and those kinds of decisions are quite difficultto make. so that very much is what is going on in thatspace at the moment. and one of the things that happens when youuse some of the new drugs is that the androgen receptor, which is verycomplicated molecule, and up the top is the normal androgen receptor. it’s got different domains and the one onthe right, which is sticking out called lbd, is called the ligand binding domain. but what happens when you treat with thesebrand new drugs, which are very powerful inhibitors of androgen,

is that you select for a variant of the androgenreceptor, which maybe present already, and it has noligand binding domain. so it actually works very strongly whetherthe androgen is there or not there. so you’re not achieving the result thatyou want. and some of the new findings are that thisparticular variant, which is ar-v7 is actually coming up afterthese therapies. and when you give those treatments, and ifthe patient has ar-v7, you can see on the slide on the left the responseof the people to drugs. so, the black line is your sort of zero line

and the yellow ones have got that variantand they’re not responding. the ones that are blue are responding, sothey’re actually getting better. so, this is a new problem which has just recentlycome to people’s notice after these very new drugs have been developed. so still haven’t really got a cure. we can prolong lives and make people sortof have a chronic disease. this is for advanced stage cancer. so let me stress that, because if it is earlystage cancer, some people respond beautifully to prostatectomyor radiation

and there isn’t another problem. so i’m talking about the advanced disease,which we are trying to concentrate on. so, let’s talk about how we work out whatto do. most patients i stratified into risk strategies,risk categories using clinical staging, which is based on how bad your cancer is. how sick you are: things like that; the level of prostate cancer antigen in theblood and the biopsy grading. if they’re under-staged, and the treatmentis given, then that can lead to an earlier recurrence.

we call it a biochemical recurrence becausethe psa comes back up and that’s a biochemical molecule. whereas if they are over-staged, they might be treated more aggressively thanthey need to be treated. so we need something to tell us what’s goingon. and we need either diagnostic tests or, perhapswhat i have not mentioned is that whilst a lot of men get prostate cancer,and as you get older, you are more likely to get it. so by the time people are eighty, eighty percentof men have prostate cancer,

but it might not be a very aggressive disease. and we still don’t have a marker which tellsus this disease is only going to cause changes that aren’treally going to affect the man’s life and this disease is going to be really aggressive. we don’t have those biomarkers yet. we’re searching for them desperately, butwe don’t have those biomarkers. so what about imaging? well, when men go to have a biopsy done, it’sactually changing now but this was the norm. they might have a transrectal ultrasound guidedprostate biopsy.

that means a probe is put in through the rectum and it goes to specific areas which are predefinedin the prostate and takes little pieces so the histology canbe done and something can be done about it. but if you then do a radical prostatectomyon men who have had those and do what is called a whole mount, which means that you cut through the wholeprostate and you go through every section of the prostate. it’s a huge amount of work for the pathologistto do that. they often find that staging that came fromthose pre-organised biopsies is incorrect.

it might be under-staged or it might be over-staged. and the other problem is that if your biopsyis taken through the rectum and the cancer is on the other side of theprostate it’s not part of what’s biopsied. so, you can miss out on it. so we need some other ways of doing it. and also within the prostate, this is truefor most cancers, but it’s especially so for the prostate,you can have multiple foci of cancers. so, there might be one at the top and onenext to it and down here. and they are all different.

they are not the same. and when they spread from the prostate toother tissues they can actually spread, say, from the prostateto a lymph node or to the bone, where they form the bone metastases. and then they can spread again. and instead of spreading from the prostate they can actually spread from the one that’sin the bone to somewhere else. or they can spread from one that’s in thelymph node to somewhere else. so, it’s an incredibly complicated diseaseto try and study

and find new methods to look after. so, for lymph node detection, they’ve beenusing mri, magnetic resonance imaging. has anyone had an mri here? yes. so you know what it is. and they’re now using special types of mri, where they look at function as well as lookingat the actual tumour. and what had been said before was that even when you use some of the functional imaging,which i’ve mentioned there, diffuse-weighted imaging,

you can’t detect a lymph node involvementunless it is bigger than eight millimetres. eight millimetres is pretty tiny, but if itis smaller than that you can’t see it. so you actually need to use nanoparticlesto enhance the mri in order to see that by special techniques. so i’ll tell you a bit more about those. so, even with the special mri, and they’venow got a new system for grading the mri, called pirad, which is the i forget what it’scalled, the predictive value. you are still missing out on some of the tumours. so in the pa hospital we’ve now got a newinstrument which is the pet mri,

so we can do positive emissions tomographyat the same time. and i’ll tell you a bit about that too. so, just to reiterate, prostate cancer iscurrently imaged by transrectal ultrasound, magnetic resonance imaging, computed tomographywhich is another form of imaging, and positron emission tomography. but we are still not getting our answers. we need better tools, both to diagnose andassist the response. and so we set about to develop new methods to improve the imaging in the lab using models.

not men but mouse models or human cancersgrowing in mice that are immunodeficient. we can actually take biopsies from men andput them into mice and if they have not got a proper immune responsethey will grow up and we can see what is going on. that is how the work’s done. so we started off using iron oxide nanoparticles and we’ve also used hyperbranched polymers. so i’ll just explain those. so we found that there is an antigen thatis a marker, a biomarker,

expressed on the surface of prostate cancercells. it’s call prostate specific membrane antigen. it was discovered a long time ago by one ofmy colleagues, who was at sloan kettering memorial then, and now in new york and is now at clevelandclinic. and it’s found on the outside of the cells. so they made antibodies to it so that theycan actually detect it. and in the normal epithelial of the prostate,the normal prostate, it’s inside the cell. and in prostate cancer it changes and goesand sits on the outside of the cell,

which means you can target it. and it is highly expressed in prostate cancerin lymph node metastases and also in bone metastases. and it is highly expressed in, what we calllethal castrate-resistant prostate cancer as well. and what is interesting about it is that, when an antibody or something binds to thepsma on the surface of the cell, it’s got a motif in the sequence of theamino acids that make up the antigen, which carry it inside the cell.

so that means that, if we can put somethingonto a molecule that’s going to bind to psma, we can carry it inside the cell. and our idea is to put a drug onto the psmatargeted nanoparticles so that we can get a higher dose of treatmentinside the prostate cancer cells, whilst avoiding take-up of drug in other tissuesso that you knock out the side effects and increase the treatment where you needthe treatment. and if you’ve got a marker such as psma,and it’s found on the bone metastases as well as on the lymph nodes as well as inthe prostate,

and you put it into the blood, it should goand find those cancers, and then it can knock out those cancers aswell, or image them. so it used to be used as a test called prostascint forfinding prostate cancer. but, unfortunately, they used and antibody which was not made against the part that wasoutside the cells but the part that was inside the cells. so it did not work very well. but they have now found that more moleculesthat bind to psma can be used for pet imaging.

what we did was we used iron oxide nanoparticles because when you use iron in mri it goes darker, so it enhances the image that you can getwith normal mri. and so i’ve shown that here. we made a particle like this with lots ofarms on it and we attached an antibody against psma orj591 which binds to the outside of the psma onthe cell. and when you inject that into a mouse, and just actually inject it into the mouseprostate to see what would happen,

because we were not really sure what we werelooking for, you could see you get this terrific darkeningeffect by the nanoparticles that are targeted. then we found that they were nontoxic to prostatecancer cells so we grew the cells and they didn’t diein the presence of those. so that’s important if you are going tostart putting them into a patient. and we also showed that they were taken upby the cells so these show fluorescent binding so we puta fluorescent marker on nanoparticles and you can see that it’s gone into theprostate cancer cells there at the bottom. and here we’ve got, because the nanoparticlesare made of iron,

there is a stain that picks up iron and soyou can see here that, in the presence of the antibody they’retaken up much better than when they are by themselves without theantibody. and you get a lot of blue staining insidethe tissue. so then we did an experiment where we hadmice that were injected with prostate cancer cells, and the prostate cancer was actually injectedinto the prostate of the mice, which is quite a tricky operation becauseit is very small. and then we either injected the mice thatwere carrying the tumours

with nanoparticles alone or targeted nanoparticles. so the nanoparticles alone are on the leftand the targeted ones are on the right. and we looked after two hours and after twenty-fourhours with mri and you can see that blackening effect thatwe’re getting; see the red arrow on the right, and similarlyat twenty four hours. so that was highly successful and showed that we could increase the abilityto see the tumour in this way. and you can see as i mentioned the blue stainbefore. up at the top is the tumour grown in the mice,

and with nanoparticles alone you got a littlebit of uptake, but when you had the nanoparticles with theantibody you got a lot of uptake. and it did go a little bit to the spleen andthe liver, but really not very much. so we were not getting very much uptake inother organs. we were only getting it in the prostate tissueoff that cancer tissue. so from that we decided that the nanoparticleswere safe in the normal prostate. and when we labelled them with the antibodies we get much better uptake by cancer cellsand that enhances the mri. and so they have the potential to be usedas an imaging tool in patients.

now some people have used nanoparticles beforein patients that are made of iron and unfortunately it caused some pain anda few toxic effects in patients. so we did all this work, but now it hasn’tmoved into the clinic, because there could be some problems. so we are trying to develop some other methods. so the next thing was we’ve used this hyperbranchedpolymers. and they’re a type of nanoparticle. because they’re hyperbranched you can stickthings on the branches. so if you think of an octopus with all thesearms everywhere,

we can put a targeting agent on it. we can put an imaging agent on. we can put a drug on that gets delivered andso on. so that was our idea, and that’s just toshow. and we tried both a peptide that was madefrom an antibody, which is a smaller molecule than an antibody. we tried the antibody and we tried a verysmall molecule. or we tried the hyperbranched polymers withnothing attached, and put them into mice in the same way withtumours.

so we wanted to compare the efficacy of thethree audience question when you say psma minus, do some prostatecancer cells not have psma? professor russell in the body all prostate cancer cells havepsma. in the laboratory we disable psma on someprostate cancer cells. we call these psma minus. pause the video here to read more. and we did some imaging studies after we’ddone the in vitro work

to show we chose the best one for in vivostudies. so we could show here by what’s called flowcytometry that we had cells that express psma and cellsthat did not express psma, which were a control one for the other. and you can see the red ones are the onesthat express psma and the black ones are the ones that don’t. and when we treated cells in tissue culture we got much more staining of the ones thatwere psma positive as you can see it each time and at each dose.

and, for example, at 120 minutes we were getting terrific uptake of the hyperbranchedpolymer with the peptide compared with what’s being taken up in thecells that don’t express the psma ligand. and similarly, with the antibody, so we gotthat working with both. and we could show again, using confocal microscopy, that we were getting uptake of the nanoparticles, which were labelled with the green fluorescencemarker. you can see there the very strong green fluorescencewith those two molecules there. so then we did a mouse experiment,

and in this time we had the tumours labelledwith a red fluorescence marker so we could see them with special imagingequipment. and we put the ones that had psma positiveon one side and the ones with psma negative on the otherside. and you can see when we injected our theranostichyperbranched polymer with the peptide attached that binds to psma, we got really good imaging of the ones onthe right, which were psma positive, and there wasn’t any imaging of the oneson the left. so now we’re not looking at red, we’relooking at green fluorescence.

but you can see in the red circle there thatyou are getting very good uptake, so that means that its got imaging potential. and in addition, after we’d done the imaging,we euthanized the mice and we took out the various organs and looked to see how much fluorescence wewere getting in any other organs. you can see here this is psma positive tumourand the psma negative tumour and the liver and kidneys and spleen. so it was quite specific for prostate cancer. and then we used a small molecule and didthe same thing.

but instead of doing fluorescence imagingwe’ve done imaging using pet. so in this case you have to use a radio-activeisotope, which is a attached to what’s binding tothe psma. and you can see on the bottom we haven’tgot any staining of the tumour, whereas up the top we have very good staining. now we use copper 64, but they don’t usethat so much in the clinic, but they can, and we just did not have the right apparatusto make the other radio isotopes. but they are now doing it in the clinic. i’d like to show you.

so, just before i move on to that, you cansee from those data that we were getting good binding both intissue culture, that’s in vitro and in vivo, where we can image the tumours better withthese psma targeted molecules. so now we’re ready, we’ve added the drugon. it’s taken 18 months of chemistry to beable to add the drug on to those and we’re ready to test them. so the chemists have been working, my colleagues have been working very hardto get them on. but before that, what they’ve done is, insteadof using docetaxel,

they used just a trial drug which is boundto the polymers with hydrazone linkage, which comes off when you change the ph. that’s the acidity. and when it goes inside the cell and goesto the lysosome the ph drops down to five or six instead ofbeing at seven. and so we can show that at ph 5 the polymerremains intact, sorry at ph 7 the polymer remains intact,but when we drop the ph to 5, we actually get it released. so that would happen inside the cell.

so we’ve now attached the docetaxel and we’re waiting to do those experimentsstraight after christmas. so we hope that it works. now the other thing i wanted to tell you isthat there is a model of prostate cancer. the only animal, only mammal, which gets prostatecancer apart from man is the dog. so mice don’t get prostate cancer. horses don’t get prostate cancer. but dogs do. and the prostate cancer that happens in dogsis like the very late stage cancer.

so it’s not like the early stage cancer. so, as i mentioned, the other thing aboutit within dogs is that the cancers that form in the boneare osteoblastic so they are making more bone, which is what happens in prostate cancer. in breast cancer, when people get cancer thatgoes in the bone, it’s holey. it’s got holes all over the place. so it’s osteoporotic instead of osteoblastic. so prostate cancer is very different in thatit forms these very unusual bone metastases. there is a lot of homology between dog andhuman genes.

more than between mouse and human as you mightimagine from evolution. and the psma is actually expressed in thedog and people have used small molecules to imagethe dog tumours. what we are going to do is there is a newlarge core pet, where you could do dog work, at the university of queensland in the centreof advanced imaging. and we got a grant to buy that recently. in talking to the vets who look after theanimal hospitals they get about five dogs a month which getadvanced prostate cancer. so we will try once we get it working in miceand use the docetaxel,

we will try it in dogs as a sort of half-wayhouse to trying to get into a clinical trial. we are also doing a clinical trial of a newpet agent, which is actually binding to prostate cancer. this was developed in heidelberg in germanyand the guys at royal brisbane hospital, a guy called paul thomas, who does pet imaging,has got all the methodology and so we’ve done a small trial where we’velooked at twenty men. we’ve done mri in the men, we’ve donepet imaging in the men, with this new agent, and we’ve done a prostatectomy and thentaken the prostate’s out and done whole mount pathology and comparedthe binding

that we’ve got by the imaging by mri withthe imaging by pet and where the prostate cancer is in the prostate. i mentioned before that you can only detectlymph node tumours that are perhaps greater than eight millimetres. with this new agent you can detect tumoursthat are probably 2.5 millimetres, so you can detect smaller tumours and thisis showing enormous promise and everyone around the world has jumped onto this new method for doing imaging of prostate cancers. and not only that, here it is with gallium.

if you label it with a different moleculewhich is called lutetium, 177-lutetium, it actually kills the cancer. the guy that developed the psma and foundthe psma as a biomarker, skip heston, who is a colleague of mine, sent me this photo that’s got some kindof award as the best photo of the year. and you can see on the right, on the lefthand side on the right, there’s a couple of tumours. the two black spots, we see that here in themiddle. and after treatment they’ve completely disappeared

and the psa has dropped from 38 to 4.6. and at peter mac they’ve done eight patientsnow who have advanced cancer, have failed all of the other treatments thatthey’ve been given, with this new psma targeted pet labelled withlutetium and they’re responding and their tumours are going away. so there is great excitement. it’s very early days, but there’s greatexcitement that this is going to revolutionise and perhaps provide a better treatment tofollow up on the other treatments. so psma pet can detect lymph nodes

and you can actually get better results inthose patient if you use the pet in order to find wherethe lymph nodes are. and one of our colleagues ian vela whose comeback from working in sloan kettering, has worked out a method for actually growingvery tiny tumours in tissue culture and they form little organoids. they call them avatards and avertoroids andall sorts of things. but he’s got them growing and he’s brought back some of the tumoursthat he got growing in america for us to work on.

and he’s taken biopsies of those tiny tumoursthat we were picking up with the psma and put them into tissue culture to provethat in fact they are prostate cancers and he’s been growing some of those up forus to do more experimental work with. so, in summary, we use the theranostics. we call them theranostics because they canbe used for diagnosis imaging and therapy. therapy, diagnostics, blah, blah. that’s the new word that’s being used. and they can be multiply decorated with variousagents to do pet and also treatments. we’re targeting them and hoping that we’llbe able to show

that the docetaxel or cabazitaxel works betterwhen it’s targeted. both can now be done with radiotherapy. we’ve attached a model drug to show thatits released at the ph that happens inside the cell and we’ll be able to verify our findingsin dogs, we hope. and we’re also conducting some clinicaltrials. so i’d just like to thank all my collaborators. these guys in the middle at the centre for advancedimaging and the australian institute of bioengineering

are the chemists who have been doing all thechemical work for us. brian and mei have been doing all the biologicalwork and the animal work. skip heston has given us some of the reagentsand we’ve had various funding. so this is the group from the australian prostatecancer research centre. it’s quite a big group now, so it’s firingalong.