>>> okay, unfortunately the doctor had a conflict and so she's going to give her lecture on september 30th. so i switched with her, and i'm giving the lecture today on small cell lung cancer, the second speaker is jim gulley, talking about prostate cancer.
so all of -- and then in terms of announcements, we now have within telepoint posted at the website, s and then the video cast is now archived, so the first lecture you can call this up on your computer. anytime. and you click past events, and
you click lectures, you scroll down to traco, you'll find lectures fro from ten years of traco, we have over 100 lectures posted. everything that gets posted stays there, and then you'll notice one interesting thing is my address has changed, and my
phone number because my office was moved last week from building 31 to shady grove, so that's good for the 20 people at shade y shady grove, now youcan pick up handouts in my office. that will help you. so we're going to lecture about the small cell lung cancer and
this cancer kills about 25,000 patients in the u.s. annually, this is about 1/6 of lung cancer patients that die, and all the other types of cancer are nonsmall cell lung cancer, small cell lung cancer is a neuro endocrine cancer. chemotherapy and radiation
therapy, the tumors get smaller but relapse occurs and tumors grow and they are often unresponsive to chemotherapy, so the median survival time is less than one year. so the small cell lung cancer, this is a biopsy specimen, you see small cells, what you
really see are nuclei in dark purple, it's very ordered. the these small cells. and then when you look at them under the eelectron microscope you see the granules, like what you see in neurons, and the small cell lung cancer as a result makes and secretes
growth factors. so lung cancer symptoms, well, the first is the cough. and then you have chest pain. your nerves are sensitive to all the inflammation, shortness of breath because part of the lung is being taken over by the tumor and you can no longer
exchange the co2 for oxygen. often times people then get infections, with bacteria, pneumonia, or they will have bronchitis and then worst of all is if you cough up blood. then that's an indication that your cancer is of one of the higher stages.
traditional it's done using chest x-ray, but then one can also do broke they can stick atube down the detroit t throat, needleaspiration, sticking a pin into the tumor to see if you get tumor cells, remove blood fluid and look for cancer cells in the fluid. you can do surgery of the lung.
and what's in vogue right now is spiral ct, a study was done by the division of cancer prevention about 5 years ago, and it showed that if you have spiral ct, and then it's treated, if the patient has tumor cells, then you'll reduce cancer incidence on the order
of 15%. and so 15% of 100,000 people is 15,000 people. so lung cancer, we're always talking about anythin bignumbers. this is a chest x-ray. here you see a tumor on the left. a fairly large tumor.
this is a ct scan where we see there's a tumor here on the left, and with treatment the tumor becomes much smaller. this is the bronchoposcopy and you see a tumor on the left. unfortunately, usually lung cancer is detected when it's in stage 3, stage 4 it's undergone
metastasis, that's bad. we can stage us ewin it usingthe ct scan, mri, pet scan you'll have a lecture about using isotopes later in the class, cancer cells will pick this up more readily. you have radionuclide scanning, bone scanning, tests for the
bone, and here in mediastinoscopy you're looking at lymph nodes for tumor cells. generally if a patient has no therapy survival time is on the order of four to five months, if you do surgery, the patient is in stage 1, increasing survival time a little bit,
radio therapy will also increase survival time a little bit. and these are some of the agents used in chemotherapy. we used to have a lecture, but now we emphasize newer drugs. agents like car bo carboplatin,the cancer cells can't correct the
genetic material once a mutation has occurred. and then other agents are inhibitors, you'll hear a lecture next week on this. this. then we have agents such as doxorubicin and we have antimitotic agents.
vinorelbine is also used and agents that interfere. so you note chemotherapy agents mechanisms.erent mechanic in the '70s clinicians started giving combination chemotherapy. this would inhibit the agent. vvh-16, different mechanisms.
the clinicians abbreviate this vp-16. other combinations, ifosfamide and carboplatin and vp-16. it was popular in the '80s, 90s, and 2000, but the result was for lung cancer very disappointing, it didn't do that much for the patient and
didn't cure the cancer. so you see here an approach to use radio therapy combined with chemotherapy, and this increased survival from 10 to 34 months, five-year survival from 6% to 30%. so a combination then of radio therapy and chemotherapy can be
beneficial in small cell lung cancer but still the patients are going to die. so initially, small cell lung cancer often responds to chemotherapy, but then the patients undergo relapse. the chemotherapy becomes ineffective.
and this is results primarily because of the field effect and with lung cancer it takes so long for it to develop, 20 to 30 years, that initially you have one clone of cells, the first clone grows out, may be responsive to chemotherapy, so that clone is killed but then
the second clone grows out. the second clone of cells is resistant to chemotherapy and that's what killed the patient. so this is what is referred to as the field effect. and then small cell lung cancer stasis, gets toma metastays is,the the brain and the patient dies
in a matter of weeks. so some cancers, the carcinogenic process is well known, such as colon cancer. but for small cell lung cancer, we really don't know anything about how it develops. and where it comes from. in the lung, there's the neuro
endocrine cells, we don't know if it's a precursor or if it's stem cells. so the carcinogenic process of small cell lung cancer is still relatively unknown and we don't have very good animal models yet to study it. we mentioned last time about
smoke as nicotine metabolites,nnk is a carcinogen, and nicotine binds to acetylcholi next receptors, and you remember akt, increasing survival of the cancer cells. they are then more difficult to kill.
and nnc forms dna aducts, cells do not undergo apoptosis, mutations accumulate. nyk can also cause akt correlation. lectureing to end this in about 30 minutes, and we're going to discuss ways about nicotine replacement therapy to
get people to stop smoking cigarettes. but you see there's a problem with that already, because if we're giving nicotine replacement therapy, the nicotine will still stimulate the cancer cells to grow. so if you do use nicotine
replacement therapy, you want to use it for the shortest period of time as you need to. and one interesting thing is we can tell who is a smoker and who is not because there's this one m metabolite which accumulates in the usual of patients who are exposed to
cigarette smoke. and so for many years the tobacco companies were resistant about the fact that their cigarettes were causing lung cancer and how did you know that a patient was actually a smoker? and then when they developed
this assa, whyy the cigarette companies got quiet because they had absolute proof of who had been exposed to cigarette smoke. and we note it's actually increased in nonsmokers who breathe in cigarette smoke, so secondhand smoke you can also
detect. one of the advantages of working in this field, i started working in it in the '80s, was that we had so many cell lines and so here at nci in the '80s, biopsy specimens from patients, these biopsy specimens were mechanically
disassociated, passing the cell suspension through steel mesh, and then the cells were cultured in a serum-free mulled medium. the normal cells died, but about one out of six of the biopsies specimens, small cell lung cancer cells would then
grow out and you have a group of cells from a particular patient. and so these lung cancer cells we see then that they need igf-1, binding to a receptor to stimulate growth. and one of the things we found is that peptide growth factor
found receptors and stimulated the growth. so over a -- in the '80s then, from 1982 to 1984, they established 31 cell lines, so we have a lot to work with in the lab. most cancers such as prostate cancer, you have maybe a dozen
cell lines, breast cancer a couple dozen perhaps, but for lung cancer we have hundreds of cell lines. and they were neuroendocrine they have high levels of bombesin pep sides. peptides. over a 20-year period, hundreds
of lines were established. we have lots of cells then to work with. and so then a goal became using animal models. one was using the a/j mice exposed to urethane that would get adenomas that appear as bumps on the surface of the
mouse lung. and so we found then that the adenomas, especially, would metabolize also lipids and enzymes would produce positives prostaglandin. here is an asay where we found we could inhibit growth with indomethacin or aspirin.
aspirin is used to prevent colon cancer. and the growth inhibition caused by the nonsteroidal antiinflammatory drug was reduced, it was also working through a receptor, not just an enzyme. here is using animal model,
whereby we have small cell lung cancers growing in a/j mice and when we inject the urethane it takes three months for tumors to form, and then by the fourth month there's about 20 tumors per lung, in the untreated animal, and in animals treated with indomethicin there was 20%
lest. if you didn't incorrec injectcarcinogen you didn't get any tumor. looking at the chemistry in these mouse lungs, we found then there was cox-2 immunostaining as indicatindicated by brown dots, in the adenoma and other areas of the lung.
this is the corresponding. the cox-2, there was intense staining in the bronchus, staining in u epithelial chris and adenoma also had immuneo-reacreactivity. cox-1 is a house keeping enzyme that's present in all cells. and this inhibits both.
with cox-2 we can induce it by adding egf, we get a substantial increase when we add egf, the antibody blocks the increase. and then the egf receptor can be cross-correlated. we mentioned previously that growth factors such as
transforming growth factor alpha and egf caused egf receptor correlation. in this case, the process occurs through a g-protein coupled receptor, and once the g-protein coupled receptor is activated it causes releasrelease transactivation.in
and it's ineubtd hade ineubthaded inhibited by a prostoglangin. cancer cells is can contrary will increase it. we added this drug, h-89, the effects were reversed. then the e-2 worked through amp. so the process is, we see,
cox-2 will cause lipid production, leading to pge-2 production, combines to receptors. it takes a few seconds to increase amp, an hour to cross-correlate, 24 hours to increase vegf production. when we look at transactivation
with the receptor activated that can activate, leading to alpha release, causing egf so this is a fascinating process then whereby one drug can cause all these downstream events and in turn cause correlation which will increase cox-2 production and this is a
cycle right here. so the traditional cox inhibitors can cause stomach ulcers and new dreg drugs were developed selected for cox-2 with minimal side effects. it is in clinical trials to see if it can function as a therapeutic agent in lung
cancer. so looking at genetic events we mentioned you have dozens of genetic events over a 20-year period and we talked about p53 and how it gets inactivated, and other things that get inactivated. p53 we mentioned plays a role
in the g-1 to s-phase and a-53 drives programmed cell death by apoptosis after dna damage, if it is mutated leading to cancer cell formation. you can have a variety of events going. this can occur in many lung cancer patients, and the rb pro
protein is absent or abnormal is 90% of the cancer patients but with rb we don't have any good drugs to treat, to have normal activity return. the fhit gene is located on chromosome 3p where a lot of lesions occur in lung cancer patients.
but fhit protein expression is associated with smoking and remains to be determined if phit is a tumor suppressor gene in lung cancer. bcl-2 suppresses apoptosis and inhibits responses to chemotherapy and radiotherapy. so one thing they are trying is
antisense to bcl2 in therapeutic trials. one company is promoting the use of antisense. all of these are trials. we don't have anything that works very well in small cell lung cancer. we mentioned there's loss of
chromosomes, especially in 3p, 4p, 4q, 5q, 8p, 9p, 10q, 13q, 17q, 22q. smoking takes so long for the tremendous genetic abnormalit, why. there's myc overexpression in 30%. one growth factor is stem cell
factor and c-kit a receptor andr and we'll be we'll be talking about bombesin. 3p delete is early, 5q, 13c and 17p deletions occur later. in lung cancer there's also micro satellite alterations, where there is a laddering of
sequences, may result from mutations in dna mismatch repair enzymes. and finally the myc genes are amplified. a more recent thing that they found is inactivation of the lkb1 inactivated in 50% of so we'll take a look at some of
the receptors. the big one is igf-1. this results in correlation, ultimately leading to erk and growth. so we had an antibody to the igf-1 receptor, it found the binding subunits at 90kdal. this alpha ir-3 functioned as a
physiological inhibitors. igf-1 works through akt signalling. so here is part two then, illustrating the receptor tyrosine kinase receptors. and then bcl-2 is then -- inhibits ability for activation.
so the growth factors increase survival of the cancer cells, so the cancer cells can undergo apoptosis. okay. scf and c-kit are present in approximately 70% of lines examined. we do have a drug for c-kit
stimulation, gleevav. we mentioned before that was used, and in high concentration can inhibit c-kit. so c-kit is a large protein, 976 amino acids, 520 amino acids. there's a 433 intracellular amino acid domain.
then in 1980, 1981, we found that high con tryinconcentrations were present in cancer cells. we made an antibody to neutralize the grow factor, you see in mice untreated as well as treated with control antibodies you get large xenograft, and they are small,
50 animals treated with 2a11. in the '90s we tried clinical trials, and unfortunately only one patient out of 13 responded to the 2a11, critica clinicaltrials were disbanded leading to the old saying of scientists have many times cured cancer in mice, but very few times in
humans. so this is why you do these pre-clinical studies, to get a drug that looks like it's going to be pretty good, but then in patients one in ten, one in 100 of the drugs that are developed and are effective in mice will actually work in humans.
so then we decided it was best to go after the receptor. and develop drugs for that. so here you see the receptor that's smaller, only 400, crossing the membrane seven times. the other only crosses once. and it binds to the
extra-cellular amino acid, note the intracellular amino acid are very few. here we only have 60. you need 400. what these receptors do is they work through signal transeption. aninthe female has twice asmany x
chromosomes as the male, are they more discuss accept it getting lung cancer? initial studies suggested that that may be the case. and here we see signal transdeduction, adding to cancer cells, the cells loaded with a dye, within 30 seconds
we see the floo flew flew thefluurescence increasing. we see an increase in second messenger production, in this case calcium, but it only lasts for a few minutes. it's a very, very fast signal. here is another way of looking at the calcium increase in cell
suspension, added peptide, within seconds calcium goes up and it stays up for a minute, and it starts to come down. and then we develop this one drug, a small molecule, you'll hear a lecture in october on small molecule inhibitors, this is one of them.
and you see that it blocks the ability of bombesins to increase. here you see the structure of the small molecule inhibitors, it's actually sort of looking like three amino acids, like a tryptophan and it looks -- this one looks more like a luceine
than anything else. so then the chemist and suit pharmaceutical firms are interested in making small molecules. we see they can block the g-protein coupled receptor but in the clinic now they use these especially for
reseptemberror tyrosine i am inhibitors. hirhere you goat get afour-fold increase and the small molecule antagonist about block it so the transactivation signal is lost. so egf receptor correlation is always upstream from erk, so
looking at that we see the ne.log increases, erk tyrosi they are revertible. if ththe drugs works for awhile but will fall off and get ma --sed. metabolized. growtif you combine them with gefitinib we see stronger
growth inhibition. it's only active on patients with egf reseptemberro receptormutations. we make it more potent by adding the g-protein coupled receptor antagonist. this is something we're looking at pre-critica pre-clinicallyand potentially it can make
patients more sensitive. and so we've already seen before how once you have the egf receptor cross-correlated you can go through the pathway, increasing survival, you can go through the pathway increasing proliferation. here we see t-i turnover
leading to increase and sark can stimulate a protease which combines to egf receptor, it looks complicated, but all of this occurs within one minute. it's very fast. then we see that a correlation within five minutes, going into the numbe nucleus to stimulate.
another way is through -- this increases motility anding migration. ultimately this leads to an increase in m met matastasis. we have much clinical trials in progress to improve the treatment of small cell lung cancer patients, but as of this
time we really don't have anything that's effective like the inhibitors. so the best thing, one time i did a test interview at an aacr meeting. we presented an abstract on nonsteroidal anti- inflammatory drugs reducing lung cancer
and so during the interview, it became very apparent what the reporters wanted to say, needed me to say, was that you took certain drugs it was okay to smoke so you couldn't get so they asked me then if i take aspirin, and i said, well, i can't, i'm allergic.
i get stomach ulcers. they all sort of started laughing. but then i said, the real thing is if you want to avoid lung cancer, just get people to stop smoking. and so now we have developed a very nice program in the u.s.
for this to occur, and one is nicotine replacement therapy, includes gum, nicorette, the patch, nicoderm cq, nasal spray, nicotrol. we mention you don't want to do this too long because nicotine will actually stimulate the growth of the cancer cells.
you want to use this and as soon as you can stop it, you want to stop it. another thing is there's very effective pills, one antidepressant is used, also sometimes on tv you see the commercials for stantix, which reduces smoking urge and
withdrawal symptoms. but smoking cessation, the best way is just to stop smoking, and this is how most people quit is they just go cold turkey, after gradual cigarette reduction. not everyone is successful the first time, so early failure is
quite common. but then ultimately, once you quit smoking, there's many beneficial effects. within 20 minutes after quitting, your blood pressure and heart rate decrease to normal level. within 12 hours, your carbon
monoxide levels in the blood return to normal. the cigarettes have a lot of co2 in them. within two days, your sense of smell and taste return. within nine months, there's a decrease in cough and shortness of breath.
within ten years, the risk of heart disease from stroke is normal. the risk of dying from lung cancer is reduced by 50%. so in the u.s. now we have 45 million smokers, and about 16% will die from lung cancer. so that's a big number.
force that's five million. but now there's 45 million ex-smokers. so that's sort of the good news, that the number of ex-smokers is increasing. and also the number of cancer survivors now is readily we now have over 12 million
cancer survivors in this country that are living. so that number is readily so we're on the right track in this country. we just have to continue to use less and less cigarettes, and then here is references that you can refer to.
and that's about it for me. thank you for your attention. are there any questions? [applause] so the small cell lung cancer was a problem in the 1980's, we had about 30% of the lung cancer patients dying from it. and then in 1985, they
developed what's called the high filter cigarette, the cigarette particles used to be very heavy, would drop down to the ground, and go deep into the lungs causing the small cell lung cancer, but once they developed the high filter cigarette, then the particles
were very small and so small cell lung cancer started to decline but adenocarcinoma of the lungs started to increase dramatically, and that's the big one now that we need to focus on. so we mentioned before about how cancer changes with time,
but in this case, you know, the best thing you can do really is to stop smoking and then the lung cancer rate will decline da mat el da. decline dramatically. we've done good in this country.
other countries are not so good. we're selling a lot of cigarettes to asian countries. and so china expects a dramatic increase in lung cancer in about 20 years, and they are working with nci as to what they can do to respond to the
potential epidemic of lung that they anticipate coming up. yes? [ inaudible ] yes, the electronic cigarettes are quite controversial. in theory, what they are supposed to do is just produce
less of the carcinogen, so they would be a safer cigarette. but, you know, no real clinical trials have been done at this point to say that they are entirely safe. and you wouldn't really know for 20 years. so the vote is still sort of
out on that. but what's good now is the spiral ct, and the goal for that is to detect lung cancer early, and so that's becoming more popular in this state. you know, that's a good thing. see, a general thing is the big pharmaceutical companies, they
don't want to have drugs for prevention. prevention because if a patient has cancer, and they give them a drug and the patient dies, they are not going to get sued. but if they go into prevention, if a patient then gets cancer they are going to want to sue
the drug company. so they don't want that, so a way sort of around that is using the device such as the spiral ct. and then if you can detect it early in stage one, the surgeon can go in, remove the tumor, and that's it.
-- a lot of lot of folks with hope with the spiral ct. >> we're pleased to have james gulley lecture today, he's it's director of clinical trials and deputy chief of the laboratory of the thermo immunology and biology, and he's in the center for cancer research, lecture
today positive toda prostatecancer, clinical update. >> thank you. it's a pleasure to be here. we have an active clinical program in positiv prostatecancer. i've been here 15 years at the national cancer institute. we're going to yo talk about
prostate cancer, first about giving you an overview about the disease, talking about local treatment options, and then talking about systemic treatment options. finally, where we're going from here. so as you -- as we go across
you'll see that we have a lot of data for some parts of prostate cancer and there's some big holes that we still have missing, like many cancers. let me give you a basic overview of the treatment now for prostate cancer.
when you're first diagnosed with prostate cancer often you have localized disease, and often you'll respond to local therapy, we'll talk about what local therapy options there are. eventually, about a third of men will develop risingd orso
tumor markers, t.s.a., following their local treatment and often will be treated with hormonal therapy at some point. eventually that hormonal therapy will initially work very nicely, but eventually, patients will start to progress despite the hormonal therapy.
then we'll talk about all of these other systemic agents that could be used in prostate cancer treatment. so what you also see is most of these patients are asymptomatic, even after they become metastatic, many patients will remain
asymptomatic until later on in the disease course. and this can drive some of our treatment decision points. so prostate cancer is the most common cancer among men, in the united states. most commonly diagnosed noncutaneous cancer.
at the the second most common cause of cancer deaths, as we'll see in just a minute. one in six men during their lifetime will develop prostate so what we have, you know, what, 40 people in this room? half men. so, you know, 20, we're talking
three or four of you will develop prostate cancer. so here you see the deaths for prostate cancer, starting with 1930 to 2009. here in 2010. what you can see is that lung cancer by far the number one cause of cancer-related
mortality, the prostate cancer is number two. you can also see that both -- well all three actually, lung, prostate and colon cancer, are the big three in men. they are all coming down, have been coming down since the mid-1990's.
that's good news. what are risk factors for development of prostate cancer? certainly age is a risk factor. as you get older, you're more likely to get prostate cancer. a family history of prostate cancer, so if you have one or two first degree relatives, you
have significantly increased risk of getting prostate first degree relatives are brother or father. geographic location, so it turns out that the united states and scandinavia have some of the highest rates of prostate cancer andations have
a lower incidence but when they migrate the incidence goes up. there's an increased risk of both lifetime risk and risk of death of prostate cancer for african-americans compared to caucasians. detection, prostate cancer can be detected based on one of
three things. you can be basessed o based onsymptoms. fortunately in the united states that's not what happens. symptoms happen, as i showed you before, really late in the disease course. most patients diagnosed in western countries are not
diagnosed based on symptoms. they are mostly diagnosed based on either psa screenings or digital rectal examination. what do i mean by whe when isay mean when i say digital rectal examination? with a gloved hand you can feel the prostate. take your thumb and forefinger,
what i want you to do is to pinch really tight like you're trying to hang on to a piece of paper or something thin. feel right here. thithis muscle part on yourthumb, when it's like that, that's what a normal prostate should feel like.
i want you to feel right over here on your knuckle. that's what prostate cancer feels like. when the doctor, when the physician, is feeling it in the digital rectal examination they are feeling for that. is there any area hard like
this? is it -- in what area is it? then they will go in and potentially biopsy that area to see if indeed there's cancer there. so that's one way we use to detect it. the other way is by psa, a
simple blood test that be done one serum from patients. now, you'll notice before the era of psa screenings, here is the number of cases per hundred thousand men. you cpn see right around here is when psa screening became widespread in the united
states. and all of a sudden you have a huge increase in the incidence of prostate cancer, the number of patients being diagnosed with prostate cancer. all the epidemiologists are saying, well, is this an epidemic of prostate cancer, or
are we just biasing it because now we can detect it earlier? there's a peak and it flattened out again. this is a by as, we were able to catch it earlier, and treat it, treat men with a lot lower burden of disease. the question is, did this
diagnosis of prostate cancer earlier using psa and digital rectal exams to screen, did that result in saving patients' lives? so there were two large prospective studies designed to look at this. there was the plco trial,
funded by the national cancer institute, the prostate lung colon and ovarian cancer screening clinical trial, and in that trial they enrolled about 75,000 men. and the men were randomized to receive screenings versus no screenings.
and after seven years, they looked -- they did a preliminary look at the data, and what they found was that in the screenings cohort, 50 men died of prostate cancer verses 44. it was a complete wash. very few out of the 76,000 men
had died from the prostate so perhaps it's too early. or perhaps there's not enough events to really get any inclusion, but it didn't seem at least in the early look, and we're going to talk about what seven years of prostate cancer means in a little bit, but at
least in the early look it didn't look like there was a big benefit to doing screening. now, there's a trial done in europe, it enrolled more than double the number of men, and they looked at those men by screening versus no screening. and they -- about the same
amount of time, a little bit longer follow-up, nine years, there was a 20% reduction in the prostate cancer mortality. so one thing that one might say is, well, this is certainly a different patient population than the u.s., certainly they used the psa screening, it's
not as widely used there, so these patients may have been further advanced. interestingly, about half of these men that were randomized to the no screening arm got their psa test done anyway. at their local physician. so it's just too widespread use
here, maybe that diluted it. we just don't know yet. the full picture hopefully will be coming out later. we'll talk a little bit more about this when we talk about other trials too. so when you are diagnosed with prostate cancer then, what do
you look at to look at the prognostic features. the pathologist will assign a gleason score. that's looking under the microscope and seeing does this look aggressive or not? the more aggressive it looks, the higher the number.
and they will take the -- they will give it a score of between 1 and 5. and they will take the most common area, the most common pattern that they see, and then they will take the second most common pattern, and together that will be the gleason score.
so you can get anywhere from 2 to 10 out of 10, although right now it's very uncommon to see anything less than a gleason 6 tumor because of the changes in the gleason grading pattern. so a primary pattern 3 is usually what you get a 3 for or a 5.
gleasonyou'll get a gless score between 6 and 10. we'll talk more about that in the clinical trials. staging for prostate cancer, so there have been some interesting staging changes in prostate cancer recently, it used to be just the anatomic
staging but now we've added in gleason score and psa. so that stage 1, you almost never see anymore because your psa has to be low and gleason score has to be low, this is probably incidental tumor. some people argue, and there's editorials, saying we shouldn't
call this cancer at all. we'll come back to that too. and then as it becomes palpable, or locally advanced, or met static metastatic, thestage goes up and positive know prognosisbecomes worse with increases in stage. so prognosis, we talked about this a little bit.
prognosis is based in part on the psa diagnosed, how high it is, the higher the psa the worse for the patient. the percent of tumor in a biopsy specimen, so if you get more than 50% of a core being positive, that's a high amount of volume of tumor.
the number of positive biopsies, typically a 12 core biopsy, so you get 12 different areas of the prostate that are sampled, and if you get two or three of those positive, that's starting to be a large amount. if it's more than half of the biopsy sample that's positive
that's high volume disease. gleason score, all of these are important when looking at prognosis. you can take the factors and plug them into different tables, nonograms online and get the predicted rate for having the disease confined to
the prostate, or having it be outside of the prostate involved in the lymph nodes and have the prediction for how the patient will do can surgery or radiation therapy, how the patient would do in terms of progression for survival, the probability.
now, the rest of the talk we're going to talk about various different treatment modalities, so for patients to have a life expectancy of less than ten years, or especially those patients who have a low gleason score, so a gleason 6 tumor, they may be candidates for
active surveillance. what do we mean by active surveillance? we mean we'll just continue to follow the psa and perhaps do additional biopsies, to see that the gleason score is not getting worse. in part, the data is based on
this study. this is a study that showed that men that were either older or men that had especially low gleason score tumors, those men actually did really well in terms of outcome. what you're seeing here is this is a box, you can see pro
portioproportion of patientsalive, 100% to 0%, shaded in gray is the overall survival. the dark line is the death due to prostate cancer. you can see that if you have a gleason score that's, say, 5 or 6, you have very few deaths proportionally from prostate
most of the men that are going to die over this, and this is a 20-year follow-up time, are going to die from other causes besides prostate cancer. if you get a gleason score of 7 or 8, you have a significant likelihood of dying from your prostate cancer, especially if
you are younger. you know, 90% of patients that die, die from prostate cancer. if they are not treated up front. so bottom line, low gleason score, you may not need to do anything. older age, even with a more
aggressive tumor, such as a gleason 7 tumor, if you're 70 to 74, you only have a 40% chance of dying from prostate cancer and 60% chance of dying from something else. so if you decide, well, you want to treat, but perhaps the patient is -- either has
survival of expected less than 10 years, you might want to treat with deprivation therapy. patients that, a, are not good surgical candidates, or don't want local therapy, or patients aggressiveve more aggressive disease but may have a lot of heart disease maybe and
therefore not good surgical candidates. this is a study looking at endrogen therapy, hormonal therapy, later on when the patient developed progressive disease. what you can see, there's a thousand patients enrolled,
hazard ratio was 1.25 favoring the use of early hormonal therapy, about a 25% improvement in survival. and interestingly, most people would say that, well, you start hormonal therapy earlier, you just are burning that bridge. what was interesting was that
there was no earlier time until what we call castration resistance prostate cancer where they progressed on hormonal therapy, whether you started up front or waited to start it. so it probably was, if you waited to start it, you
probably developed such a bulk of disease that when you came in with a hormonal therapy, it blew through it more quickly. survivalse specific file was was not different even though overall survival was, overall survival is the primary end point.
for patients with a predicted survival of ten years or more, that is actually most of the patients that we see, with prostate cancer, even though median age is 71 years old, these are the treatment options. yooptions.
you can do surgery, surgical remove, external-beam radiation therapy or brachyperp. first, surgery. so as i mentioned, surgery, radical positive thaprostatectomy is surgical removal, done with a variety of different approaches.
the most common side effects are actually impotence, which we'll talk about, and incontinence. let me mention before we talk about side effects, let me mention a recent trial that was published a couple years ago, 2011, in the new england
journal of medicine. in this trial, patients were randomized to receive surgery, versus just watching the and not doing surgery. you can see that there was an improvement in survival, if you got the surgery versus this watchful waiting, which
basically was treating the patient later on with a variety of treatment options. this was the overall group of but what's even more interesting, i think, this subgroup analysis, that is if you just see older men, men greater than or equal to age
65, we see there's no difference here in either deaths from any cause, death from prostate cancer, or time to met' ma metastasis. in younger men you see this splitting the curve that there's less competing causes of mortality, the less people
are going to die from their heart attack or stroke, and more people are going to be -- end up being affected by this. it appeared that the majority, if not all of the benefit for this surgery, was in the younger patient population. we'll come back to that in
another trial where we see similar type of trend. right now we'll come to it, so this is a trial that was just published late last year, less than a year ago, and this was the pivot trial. this is the prostate intervention versus observation
trial. what was interesting about this trial, you see there's really no big difference between observation and radical prostatectomy. if a patient is getting no surgery, and this is a u.s. trial, the other trial was a
european study. so less of a difference here in the u.s., perhaps because we're finding the patients earlier, we're doing the psa screening, and that would suggest that maybe what we need to be focusing on is who has that lethal phenotype, patients that
have the disease that really need to be treated. maybe we're finding too many patients here in the u.s so what you can see in this pretty busy plot, i want to point out, this is the same thing for both of these. overall survival, the primary
end point, you can see those men had a psa greater than 10, the more advanced disease, those patients had a stat statistical benefit from surgery. conversely those men with the low risk disease, usually low gleason and low psa, and low
stage, they appeared to have no benefit, maybe even slight detriment, from getting surgery, the intermediate high risk appeared to have the benefit of surgery. what we need to focus on, i think, is patients that have the alit lethal phenotype,maybe men
of those that have less advanced disease can be watched. there's lots of studies, it's actually changed the paradigm -- arepatients are dealing being treated in the u.s let's talk about radiation therapy.
so what is external-beam radiation their? radiation therapy? radiation from outside the body. a variety ofom a "variety" of studies. there's a new -- ten years ago this was new, intensity mod
lated radiation therapy can allow for a high amount of radiation directly to the tumor sparing most of the normal tissue. the most common side effect with radiation therapy also includes impotence and rectal irritation.
so like surgery, impotence is a big issue. so just to show you here the radical -- sorry, radiation therapy in the lighter gray and radical prostatectomy in darker, you can see here both of them are pretty bad overall when it comes to impotence.
there's a quicker decline with surgery, and then there's a plateauing out that takes longer to get there, to come down, with the radiation but they both end up with about 50% of the men having decreased ability to get or maintain an erection that is sufficient for
vaginal penetration. why is that? so turns out that the neuro vascular bundle that runs right next to the prostate here, this is the prostate right here, enervates the penis and allows for erection. if you were to come in with
surgery, and cut out this prostate, that you would be interfering with that, especially if the tumor is near this part of the prostate. certainly the same thing with a radiation, where the radiation goes through there too. so how do they do in terms of
incontinence? this is urinary incontinence, dribbling or some leakage of urine? you can see that it's much worse than surgery than it is for radiation but they both take a little bit of a hit and how about for bowel bother?
if you get irritation, it's worse with radiation, you can have patients that have multiple small bowel movements every day, it's not as bad as incontinence or impotence. and brachytherapy, implant of seeds in the prostate, you can see the pelvic bones here, the
prostate has multiple seeds implanted, radioactive, permanently left in the prostate that give off radiation over a erred pooh of a period of a month. after that the radiation is gone. the nice thing for patients is
this procedure is a one-day procedure. it can be done on an outpatient setting, and doesn't require them to be hospitalized like surgery does, or doesn't require them to come back monday through friday for 15-minute likes external beam
radiation for up to 8 weeks. but really should say brachtherapy is indicated for low risk or perhaps intermediate risk tumors. high risk there's no defined role for brachytherapy, it certainly by itself. it can be combined with special
beam radiation. now how about bowll locallyadvanced diseases? perhaps you could do conservative management. for patients that elect radiation therapy, one can give radiation plus hormonal therapy and there's also data for
surgery, hormonal therapy with let's talk first about the radiation therapy. i'm going to give you one example, because of time of a clinical trial. this was the first clinical trial showing an improvement in overall survival, if you
combine hormonal therapy, endrogen deprivation therapy this trial was small with at least four trials since, randomized trials, that have shown much the same data. and there was improved outcome when you gave the combination, both in terms of local control
of the tumor, so less symptoms, locally. met'asasis free survival, and most importantly, overall survival. 62% versus 78% at five years, this is highly statistically significant. let's talk about surgery, there
have been a variety of studies looking at hormonal therapy, and there's been nothing that has improved -- has had an impact on clinically significant end points except for one trial in which patients with lymph node positive disease were at time of
surgery, and this is just microscopic disease, so at surgery they took out the prostate, they took out the lymph nodes, and they went carefully, the lymph nodes were not enlarged but they carefully looked at this under the microscope and found there were
some cells of prostate cancer within the lymph nodes. they found that if you put those patients on hormonal therapy right away, those patients actually lived longer than patients who didn't get the hormonal therapy right away.
and this trial was closed early because of the improved overall survival that was seen. 98 patients were enrolled, 12 years of follow-up, 17 of 47 patients died in the immediate androgen deprivation therapy, and only 28 out of 51 died in delayed therapy group.
this was a hazards ratio of 1.84. so 84% increased risk of death. in the delayed group. now, i mentioned, it was not fully enrolled and this probably is worse outcome than you would expect for this group of patients, so there are some
people that question this data but it remains the best data to date. the only randomized trial to date in this patient population. so it is considered standard of care. how about patients that undergo
surgery and now are found to have still disease left behind? surgical margins are positive, a pathologist sees the cancer going into the edge of the tissue that's obtained. turns out these patients are also benefited if they start hormonal therapy early.
this is a trial enrolled about 425 patients, they had positive margins, but no lymph nodes that were positive. if they started hormonal therapy right away, sorry, not hormonal therapy, radiation therapy, right away, so radiation to the local area,
you had improved survival compared to observation, statistically significant. this is at ae median follow-up of 12 1/2 years, let's talk about patients, we talked about local therapy, how about patients whose psa starts to rise, a issued tha -- a thirdof patients
not cured by local therapy. what happens with those patients? what are the actions for those well, this rising psa could be due to local disease, right there at the level of the prostate, and maybe those patients could get radiation
still if they've had surgery before. or it might be metastatic disease and that could be metastatic disease we can see on scans or perhaps not. options include local therapy, hormonal therapy or following the patient.
it's difficult to look at this group of patients and say if it's going to impact their overall survival. that's because of this data this is a trial where about 2,000 patients with radical prostatectomy were followed, and 304 of them experienced a
psa relaps, rising psa. of those 304, 103 went on to develop metastatic disease. based on this data set, this data set is from hopkins, a single institution where were treated by a single surgeon, none received hormonal therapy before having clinical
metastatic disease, it allows for looking at the natural history of prostate cancer. the median time from psa elevation to metastatic disease was 8 years. that's a long time. median time to death after that was an additional 5 years.
you have surgery here, average of 2 years before the psa started to rise, average of additional 8 years before they develop metastatic disease, and average of another 5 years before they die. now, a lot of these patients have low gleason scores, they
were not very aggressive clinically. this is kind of changing as we are moving into the era where we're doing surgery on these more aggressive prostate cancers and leaving the gleason 6's to just watch and follow. we'll see how this evolved over
time. but that becomes difficult then if you have that long of a follow-up, are you really going to impact survival? perhaps some patients, especially if their psa is not going up quickly, you can probably just sit on these
patients and watch and wait and wait and hopefully not have to do anything for years. once somebody develops metastatic prostate cancer, really that's where a lot of us have our -- that's the trigger -- hormonalart har money it typically spreads to bone
and lymph nodes did yo but cango anywhere. only 40% of patients with metastatic prostate cancer have soft tissue disease. the rest of them have bone only that is disease that is just in their bones. that is not -- we can't really
measure how big those lesions are based on the bone scan. it's difficult to do our traditional studies where we shrinkage of tumors.of the psa books a good marker to see how a patient is doing in terms of therapy. let's talk a little bit about
the cornerstone for treatment prostate cancerroperty taste that led to a nobel prize by dr. huggins here. basically what he showed was that in patients with advanced prostate cancer, he took a large number of patients that had advanced positiv prostatecancer,
decreased testosterone levels, using sin the syntheticestrogen, and they got better quickly, the tumor markers, that was before psa had been identified, but the tumor markers came down significantly. what he did was something that probably wouldn't pass our
irb's today, but this was in the days before there was al reviewnt institute jag board authority. he gave the same men back testosterone, their symptoms came roaring back, the pain they were having became much worse.
he showed very convincingly that testosterone was very important in driving prostate cancer growth and symptoms. and based on that in 1966 he won the nobel prize in medicine, or shared it. let's talk about hormonal therapy, what is it?
well, this is a representation of a prostate cancer cell or prostate cell. you see the sig cytoplasm, thenew nucleus. the testosterone comes into the cell, within the cell testosterone is converted to d.h.t, and then it binds to the
androgen receptor, in the cytoplasm of the cells. once you bind the androgen receptor, you dimerize, you get heat shocking chaperones that will bring the androgen receptor into the nucleus, and it will bind to androgen response elements and drive out
transcription and translation of the cell and so you'll get okay? this anabolic process is driven by this testosterone, so by knocking out testosterone, you're going to then inhibit all of this pathway and inhibit transcription translation, et
cetera. so there are several different ways we can knock out the testosterone by directly lowering the amount that's made in the body, or we can actually interfere with the pathway by hitting the androgen receptor. testosterone-lowering therapies
depend on the fact that the hormone made in the pituitary can be lowered. if you give either a gnrhing agonist or antagonist you can decrease the levels of testosterone, because gnrh is released, if you give an agonist it's going to be --
you're going to get transient increase in testosterone levels before they drop to nothing. there's only one approved antagonist, and it requires monthly injections rather than injections every three monks, with the gnrhing aist in. orchiectomy is another option,
removal of the testicles, where you make 90% of the testosterone found in the body. so side effects of hormonal therapy, androgen deprivation therapy, there's a long list. but the main ones that you will hear men complaining about, include the decreased libido,
decreased sexual drive, erectile dysfunction. hot flashes are a big one. it's similar to like when women are going through menopause. very similar in terms of intensity and type of symptoms that they get from the hot flashes, and it's very similar
in terms of the pathophysiology, we treat it the same way we treat him going through hot flashes, similar types of therapies can be used. you can get some increased fat deposition and decreased muscle, you can get a little bit decrease in bone mineral
density like when women with going through menopause, they can be in acceleration of bone loss. and you can potentially get an increased risk for diabetes and there's some controversy surrounding whether or not there's an increased risk for
heart disease also. the other way we with interact with the an androgen signal pathway is broo blocking the receptor.error, thosthose of these drugs willbind to the androgen receptor, the earlier classes of drugs just bound to it and prevented the
testosterone from binding to a certain extent. some new agents, what we're tall about, their benefits in just a minute. so all of them have a similar mechanism of action. they bind to androgen receptor and can decrease the go signal
for the prostate itself. there's other hormonal agents. ketoconazore has beeole hasbeen used until recently abirateron was recently approved, increasing the synthesis of adrenal male hormones, we'll talk about that in a little bit. so now let's move to metastatic disease,
treatment options for a patient with metastatic prostate cancer, who now started to have symptoms. until 2004, really nothing was shown to improve survival in men with prostate cancer that had me metastatic disease, very disappointing.
some aeurbts wer agents wereapproved based whatcreasing symptoms, that they showed was if you gave this older chemotherapy drug, you could actually improve the quality of life of men for a longer period of time than if you just gave the bread in glucocoticoids such as bread in
this season. prednisone. this became the standard of scare and helped men get through some of the symptoms they were having. so because of that, it was used as a standard agent compared with a newer agent, also known
as docataxel. all of the groups got prednisone to even that out. what they found was that if you give the docataxel every three weeks you get an improved survival, the weekly docetaxel fell in between. there was a 12 r. ar atwo-and-a-half
month increase in survival, 22% reduction in the risk of death if you got docataxel. i should also mention that that may be an underestimate of the true benefit, because patients who received it at progress with allowed to get the docataxel, and half did.
cabazitaxel appears to have activity. they looked at 750 men with metastatic prostate cancer who progressed after receiving docetaxel. what they found was there was more fox es city in the -- there was more toxicityx is
but there was an improvement in you can see here about 30% improvement in the mortality compared with -- or overall based on this, the f.d.a. approved this in 2012. let's talk about abiraterone, also recently approved in 2012. what you can see here is that
the way it works is by decreasing the synthesis of the male hormones, androgens, both within the adrenal glands and something we've identified in the last three or four years is tumors have enzymes that can make the androgen themselves. positivthey are making theirown
gasoline, they are fueling their own growth. this can lower the testosterone levels to very low levels in the serum, but they can lower the intracellular levels substantially, it appears in patients treated with just standard hormonal therapy, the
intracellular androgen levels can still be relatively high. so in this publication, the new england journal of medicine, 2011, you can see the overall survival was substantially better, you see a 35% reduction in risk of death, and this is following chemotherapy, the
time to psa progression was also longer, an ten versus six months, and progression survival fiving th better withthis versus placebo. the f.d.a. approved it for prostate cancer. now we'll talk about the final hormonal therapy agent that i
want to mention. this is another agent that is an androgen receptor antagonist recently approved based on improved overall survival in the last, as i'll show you, in the last you few years we've had a large number of approvals.
this is an androgen receptor antagonist with a high affinity for binding to the androgen receptor, bicalutamide, 80% of the market share before this, you can see much better with mdv 3100, not as good as the gold standard, but you can see there's less likelihood of this
androgen receptor complex being it doesn't bind to the androgen response element and can't initiate transdescription and translate, where with bicalutamide you get some, you what did this drug look like? early on in the initial phase one and phase two studies, what
you saw was there was a substantial proportion of patients that had decreases in psa better than you would see with chemotherapy, for instance. you see a little over half of the patients, chemotherapy naive, or after had decline in
psa. so in another landmark article published last year in the new england journal of medicine you see there was improvement in overall survival and radiographic progression-free survival if you received this. this was better than the other
data. the last approved -- well, no. we've got two more approved agents. the last agent that we're going to talk about, patients with metastatic prostate cancer, as i mentioned, they often have disease that is predominantly,
if not solely, visible in their bones. you can see this is a patient, this is a bone scan, you can see multiple lesions on the skull, the white areas represent prostate cancer lesions, here is the rib. here is a frontal view.
there is a bone-seeking agent that was just approved this year, called radium 223, and alpharad,n waden was a name itused to go by. now it's xopiga, with an x. it'if you look at the periodic table, it's in the same row as calcium.
this radium looks to the body like calcium, so anytime that there's active ongoing turnover of bone, it's going to pull in this radium in it there, and in these osteo blastic lesions that prostate cancer tends to have, there's lots of ongoing active turnover incorporation
of radium into the bone and because it's an alpha emitter it will go and actually kill the cells it comes in contact with. so again this is published in the new england journal of medicine just this year, a few months ago.
you can see overall survival substantially better than placebo, that's a very good clinical end point. also substantially better. so in the final few minutes we'll talk about therapeutic vaccine. now, this happens to be the
area that i like the best. the area that i'm involved in, in my research here at the intramural program. there is one approved therapeutic vaccine for prostate cancer, an and that is know as provenge, the trade name.
the idea behind this and all therapeutic vaccines is develop an immune response whereby the patient can recognize and attack the tumor. the immune system can recognize and attack it. how do they make this particular drug?
well, take a patient, that patient undergoes removal of blood, it takes and they spin down the blood and take out white blood cells and give the patient everything back, mass plasma, platelets, et cetera. they take -- they target what's prostatevirtually all positive
cancer cells and have a fusion. they put that in with the cells and that causes these white blood cells to become activated, and the androgen presenting cells within that can become activated, generating an immune response. process takes three days and
the process is repeated every two weeks for a total of three times, so over a erred pooh of month, that's an entire treatment course for a patient. that's complicated, but there was a large face phase 3study, patients received either this vaccine or placebo, and the
primary end point was overall you can see that patients that received the vaccine actually lived longer. there was a 22% reduction in the risk of death and the improvement in survival was four months. so based on this, the f.d.a.
approved this. what we're working on here is a different strategy. rather than going through all the logistical complicated processes of being apharesis, we're taking an off the shelf approach. we've designed, engineered, a
vector. psa found in virtually all prostate cancer cells as well as jeeps fo genes for othermodels system the immune sis step revved up, putting into a viral vector and all we can do is take that out of the freezer, thaw it and inject it like a
flu shot. it's simple but imunologically advanced vaccine. designed for the impact trial, the provenge trial, vaccine versus empty vector, the progression for survival was the primary end point. overall file wa survival wasthe
secondary end point. you can see a nice improvement in overall survival, 8 1/2 months, 44% reduction of risk of death if you receive the so this has led to an ongoing phase 3 study. but what was interesting between -- with this study, and
with the provenge trial, what they had in common, there was no improvement in progression-free survival. the survival, overall survival, was clear and significant, clinically meaningful, but the progression-free survival, the time until the patient's
disease started to get worse, was not any different between the two arms. there was no substantial decrease in psa like you saw with the others. i think it's important when we think about what might be going on here, to think about the
differences between therapeutic vaccines, immuno therapy and conventional therapy. first of all, cyto toxic therapy targets a different environment. immuno therapy targets the immune system which in turn targets the tumor.
perhaps in part because of this you may see a delayed response. in fact we see that often where we patients getting some newer immune checkpoint inhibitors have disease that gets substantially worse before going down to nothing. with therapeutic vaccines you
expects to see a memory response, that's in fact one of the goals, but you don't expect to see that with conventional conventional therapy's often limited by fo toxicity. perhaps in part because of the delays but pr prolong responseyou kinetice a different ken itic
profile. we looked at data. extremes we found what we came in with our most aggressive chemotherapy regimen, what you see is a dramatic decrease in the tumor volume in the majority of patients treated, remaining down for a variable
teared of time. when they started to progress you could accurately define when the patient was going to die and that growth rate was pretty much identical to the growth rate in the study. when you came in with immunotherapy you didn't see
this big decline in the tumor growth rate. sorries thsorry, the tumorgrowth rate. you sawe an eventual slowing down that could increase survival, brings to mind the tortoise and the hare, slow and steady win the race. one example of a patient that
with treatment with prosvtvac and early on when they were diagnosed, the rate the psa was going up at, they had surgery, it came down nicely. it's going up at the same rate eventually they had vaccine, you can see the psa continues to go up and comes down
beautifully but when it starts to go up after the three vaccines, it's going up at a slower rate. they got irb approval to give the patient another three vaccinations, and you can see here it appears to have flattened out again.
in follow-up data from that, that will be coming out this year, it's in press right now, the psa dropped down to less than 4. how do we put the vaccines into juxtaposition with the other approved therapies? well, you have the chemotherapy
vaccine, hormonal therapies, and this was just approved this year, all the aeurbt agentsapproved recently. you can see the decrease in the hazard ratio, which is a decrease in risk of death. so we get a 24-37% reduction of risk of death.
improvement in survival between 2 1/2 and 4.8 months, wit or44% reduction in death, 8 1/2 month improvement in survival, based on phase 2 data. there's a phase 3 trial going on right now. what i would also point out is that the number of patients
that have to stop due to adverse events is low with the vaccine compared with the other therapies. but also the portion of patients with declines in psa, very low in the vaccine compared to the other therapies, as we already know.
so based on this data there's an ongoing phase 3 trial, that will enroll 1200 patients looking it's a overall what we've talked about is treatment for localized disease, radical prostatectomy, radiation, brachy therapy, hormonal therapy, standard of
care to combine with radiation therapy following radical prostatectomy and in patients with metastatic disease as prime airplane therapy. primary therapy. we talk about vaccines, patients with more advanced or perhaps reserved for
symptomatic prostate cancer. we talked about these brand new agents, and this radium 223. and finally what we didn't talk about was zoledronate, they do not improve survival but can decrease of chance of them skeletal relatedal related events.
thank you and i would be happy to answer any questions. a good question. the question was can you get vaccinated for prostate cancer before you're diagnosed as a preventive?t i we think about flu vaccines or hepatitis to prevent you from
getting hepatitis or cervical cancer vaccine, the hpv vaccine that hopefully is going to eradicate cervical cancer as we know it now. yes, in theory, yes. in kneer theory they could workto generate a response to decrease the chance of getting prostate
i don't know that we are ready yet to do a trial of that magnitude that would prove effectiveness of this. it's going to take a vaccine like what we have that should be a lot cheaper to do, i should just mention there has been been some controversy
because this vaccine, because of the logistical issues associated with it, it is very costly. it's about $93,000 for a treatment course. so that works out to $31,000 per vaccine, you get three over the period of one month.
other questions? i saw a hand. right. it's a good question. so could you treat benign prostate conditions with this? or could you treat pre-cancerous lesions with somebody that's at high risk
for developing cancer. the answer is potentially we actually are talking with the prevention, prostate cancer prevention program, to see if perhaps we can use this in patients, we might actually try it first in patients who are candidates for active
surveillance. and then see if we can come up with parameters that would enable us to do a larger study, the parameters would be can we take and decrease the pro poergs oproportion of patientsthat go on to get surgery or if we can prevent them from having to go
through a morbid procedure, radiation or surgery, that's a good thing. tapperhaps we could bygenerating immune response that could wipe out some bad acting cells we could prevent or delay that. that would be a good thing. foror other benign conditions,
potentially one could use this. you know, could you one day be able to get a vaccine that is potent enough or mod light modlate the immune system for a removal of the prostate rather than by surgery, you know, it's not -- you might say that'sen science fiction.
stay tuned. some things we have going on are really looking interesting. so potentially there's certainly patients that get organ transplants. we know the immune system is capable of annihilating that organ.
how to turn on the immune system and get it to react to that, i think we -- i think in the next decade we could make significant advances towards that. so two things. the kotaconozole is f.d.a. approved for fingernail fungus,
other fungus. it's the same mechanism used to fight fungus, so it's a sterol, the steroid enzymes are hit, but a much higher dose than we use to fight fungal infection. at the higher doses, it affects a lot of the adrena adrenalsteroid synthesis, and by doing show
shuts down several things. it can shut down not only the moregen and other sex more gland too.enals grand and because of the issues with that there's a lot of drug-drug interactions, so probably soon to be relegated to the history books in the treatment of
prostate cancer, because effectsmuch fewer side with others, if you add it to patients on abutarone there's less drug interaction and survival, never known fo shownfor. r. ketaconozole. thank you very much.
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