Cervix Cancer Treatment

professor mark saltzman:so, what i'm going to talk about today and thursday is twotopics, which what i hope to do is sortof bring together some of the information that we've beentalking about over the course of the term.to do that, i want to focus on two areas, today talk aboutcancer--a big subject, and so we'll just scratch thesurface. the main point that i want tomake is how some of the technologies that we've beentalking about over the course of

the term are having an impact oncancer diagnosis and care, and to sort of point to someareas where they'll likely be more progress and opportunitiesfor progress in the future. then, on thursday,we'll do the same thing but talking about the subject ofartificial organs. one that we've brushed on acouple of times through the semester, but just try to spendsome focus time on it on thursday.section meeting on thursday afternoon, we'll do a coursereview.

i'll be there for each of thesections. i'll just be leading adiscussion about what we've covered in the course and whatkinds of things will be on the final.any questions? you know what's describedhere on this slide, that cancer is a deadly and,unfortunately, not uncommon disease.these are some statistics from 2006 collected by the americancancer society. one of the things that we dofairly well as a nation,

now, is keep track of cancercases and progress. this has been an important partof our learning about where cancers occur,what are the causes and what treatments work and what don't.the american cancer society has been a big part of that effortto collect information on where cancers occur in the country,in what people, in what age groups,and to provide that information for people that are working onresearch for cancer. this just summarizes someof that information.

for 2006, new cases of canceryou can see over a million new cases, deaths from cancer abouthalf a million and roughly equal between males and females.here's some common types of cancer occurring in females,breast cancer in both males and females, lung cancer,and in males only prostate cancer.the statistics are alarming. you look at the number ofdeaths that are caused by cancer and if you want to learn moreabout sort of that, i urge you to go to theamerican cancer society website

which is listed here.just a few facts about cancer that you probably knowsomething about this, it's now the most common causeof death in the u.s. and that's true in manydeveloped countries. cancer and heart disease havebeen neck and neck in terms of the number one cause of deathsin developed countries for many years now.it looks like cancer is winning and we'll talk about that in aminute. cancer's caused by mutations ingenes that control cell growth.

you know that a cancer orformation of a tumor is an unwanted or uncontrolled growthof cells. cell division runs amuck andcells don't stop dividing under circumstances where they'resupposed to. so, you get--a mass is formedand that mass is--it represents the unwanted growth of cells.the mutations that cause cancer, that cause these defectsin cell growth, can be either inherited orenvironmental. we know that there are thing inthe environment that cause

cancer, some viruses can causecancers. one of the clearest links isbetween human papillomavirus, a sexually transmitted diseaseand cervical cancer in women. there is a new vaccine for hpv,human papillomavirus and it's expected that this vaccine whichwill prevent spread of the virus will also significantly reducecancer cases. other kinds of viruses arelinked to liver cancers, for example.chemicals can also, in the environment,can also cause cancer,

and we'll talk more about thatin a minute. most cancers also involve somegenetic changes that can be either acquired or inherited.you know also that cancer can run in families.the risk of certain kinds of cancers, there's a genetic basisfor that. in the u.s.,the lifetime risk of cancer is 1 in 2 for men.so, half of men will have some kind of cancer,and 1 in 3 for women. that's a pretty impressivenumber.

the age adjusted mortality ratefor cancer is about the same in the 21st century as it was 50years ago, that is, the rate of death fromcancer hasn't changed very much in the last 50 years.this, in spite of the fact that there's been a lot of attentionto cancer and learning more about cancer,and its causes, the basic biology and in tryingto design new methods for diagnosing and treating cancer.but overall deaths haven't changed very much;we've made progress in certain

kinds of tumors but not inothers. this just, i think,reflects the fact that both cancer is a heterogeneousdisease. you know that it occurs in avariety of sites throughout the body, but in each of those sitescancers can be quite different. it's not one disease but itsfamily of diseases. because of that,it's been hard to make progress in treatment because all of themhave slightly different characteristics.this just illustrates that

last point a little moreclearly. change in u.s.death rates by cause from 1950 to 2003, so over that perioddeaths from heart disease went down dramatically.deaths from cerebral vascular diseases, so deaths of thecirculatory system in the brain, so this is mainly stroke andaneurisms down dramatically. deaths from infectiousdiseases, we talked about vaccines several weeks ago whichhas a big impact on mortality from infectious diseases,also down over that years.

deaths from cancer stay aboutthe same. while we've made greatprogress, we're not yet at the point where we're changing theoutcomes from cancer very dramatically.i mentioned a few minutes ago that exposure to chemicalscan cause cancer, and you know this.one of the most well known exposures that's clearly a causeof cancer is tobacco use. this is tobacco use mainlythinking about cigarette smoking, but the same thingcould be true of any kind of

tobacco use.smoking in other--cigars or chewing tobacco also causescancer because the chemicals in cigarette smoke or in tobacco,in particular. some of the tars that areassociated with smoking cause cancer of the lung inparticular. this was first noticed bylooking at epidemiological data. we talked about public healthand epidemiology a few weeks ago where you look at how diseasesappear in populations and you try to figure out why things arechanging.

here's as cigarettes wereconsumed more in the u.s., you can see the trend incigarette consumption going up over time from 1900 to 1950.then, lagging behind that by about a period of 30 years,is a dramatic increase in lung cancer.first among men and then among women, and the reason for thatis because cigarette smoking was initially more popular among menthan among women, but advertising and the women'smovement changed that. cigarette smoking becamesomething that everybody could

do.it was acceptable in polite society for women to smoke,and they were targeted by manufacturers of cigarettes.special cigarettes were made for women, they're special insome way but not in their ability to cause cancer,they're all the same and so female lung cancer still rising.you can see we've made progress in male lung cancer,mainly by reducing the number of smokers, but that hasn't yethappened in women. evidence first came fromepidemiology but then after it

was realized that there was anassociation between cigarettes smoking and cancer.then, you can start to look more closely and try to figureout what the molecular cause of it is.we now know quite a lot about how the chemicals in smokecause these sorts of malignant transformations in cells thatlead to cancer. the evidence is pretty clear.the main point that exposure to chemicals can cause cancer.this just to try to put in perspective where cancer occurs,what are the most frequent

causes of cancer that lead todeath, and in both men and women,lunch cancer is number one. after that it changes the topthree in men being lung, colon and prostate;in women lung, breast and colon and accountingfor just those top three, the large majority of cancers.cancer of the pancreas is much less common but because it's sodifficult to detect and we'll talk about methods of detection.the pancreas is an organ that's deep within your body and it'shard to find when things are

going wrong with it.because it's difficult to detect cancer of the pancreas itvery frequently leads to death, and of course this is in thenews now because this is the kind of cancer that patrickswayze has. life expectancy when you havepancreatic cancer is--life expectancy is very low becauseit's usually in an advanced stage when it's discovered.cancer cells are different, so what makes all these cancersat different sites similar is the similar characteristics thatthe cells that form cancers

have.i mentioned already that one of the things that characterizescancer is that cells divide abnormally.they divide, usually, more rapidly.we talked about, several weeks ago when we weretalking about cell culture, we talked about cells that youwould isolate from tissue and they would grow at a rate ofabout by doubling their number everyday if you maintained themin culture. cancer cells can grow muchfaster than that so they have

mechanisms for dividing veryrapidly. more importantly probably,they don't stop proliferating when they're supposed too.you know, from what we've talked about before,that there are cells that are continually dividing andreproducing within your body. cells in you intestinal tractfor example, cells in the liver, cells in the kidney continuallydividing, cells in your skin. but ordinarily your skin staysthe same size that it is because are cells are dividing but theyknow when to stop.

they stop when they reach theright density, the right shape,they know where they're supposed to be.cancer cells don't, they continue to divide evenwhen they get signals that they're supposed to stopdividing. because of this tumors form,abnormal growths--the organ of--origin becomes larger thanit ordinarily would. they generally don'trespond to signals that are provided by neighboring cells,we talked about cell

communication and how importantthat was for the life of a tissue.for your liver to be your liver and your brain to your brain,they don't just have the right cells there but they have cellsthat are communicating in the right way.there's a loss of that normal molecular communication when youhave cancer. they don't differentiatenormally but tend to remain as immature de-differentiated orundifferentiated cells. what's this like?this is like we talked about

stem cells, stem cells are lessmature than differentiated tissue cells.they grow rapidly; both stem cells whichself-renew and cancer cells. they don't form mature types ofcells and there's a lot of linkages know known between stemcells and cancer. some people think that withinany individual tumor, there are cancer stem cellsthat really are the most important ones to treat.if you get rid of even the bulk of cancer cells without gettingrid of these very stem like

cells in cancers the tumors willregrow again. so, normal differentiationlike stem cells is a problem with cancer cells.they don't adhere readily to other cells and extracellularmatrix, they do not become specialized and die.because cells in your skin are continually going through notjust birth, not just growth of new cells but death.there's skin cells that are dying and being shed from yourbody all the time. cancer cells don't undergothose normal processes of cell

death that lead to regulation oftissue structure. if a cancer forms,it tends to go through different stages and that thiscell, for example, in this tissue is apre-malignant cell. if it becomes malignant,it will start dividing and growing out of control and youcan see that here. that tumor that forms at theinitial site or the site of the origin of a cancer is called theprimary tumor. these tumors,if they grew,

would ordinarily stop at a sizeof about one millimeter, very small.you wouldn't even be able to notice them, maybe,if they're only a millimeter or so in size.they don't grow beyond that as a cell mass because they can'tget nutrients, oxygen, glucose,the things that the cell needs, amino acids.the things that it needs in order to produce new cells can'tget in because those are normally provided by thebloodstream.

when the cell is just dividingout of control there's no blood supply.many people think that tumor size would be limited.cancer wouldn't be such a problem, except for the factthat cancers at this stage, as they move from this primarystage to invasive cancer, they develop an ability tostimulate the growth of blood vessels so,now you can see blood vessels are growing into and throughthis tumor, they develop their own blood supply.they're able to get nutrients

readily, and this is when thegrowth of the tumor really starts to take off.we'll talk about some therapies that block this process of newtumor growth called angiogenesis.many people think if you could block that process selectivelyin tumors then you could halt all tumors to a very small sizethat would not cause problems. an additional stage afterangiogenesis that some tumors can go through is a processcalled metastasis. that's where tumor cellsactually leave their site of

origin and travel to otherplaces in the body. that's shown schematically inthis cartoon here. a tumor cell entering thecirculation, it can flow through the circulation,and maybe get lodged at some distant site and begin theprocess of tumor formation at that distant site.this is obviously a bad thing because maybe you can treat theprimary tumor in a variety of different ways which we'll talkabout in just a minute. once it begins to spreadthroughout the body becomes much

more difficult to treat.you have not just one tumor, but potentially hundreds orthousands of tumors that are forming throughout the body. the treatment fortumors--for cancer--depends very much on what stage it's at whenit's identified. for every kind of cancerphysicians, oncologists, have developed classificationmethods for talking about, to each other,about what stage the cancer is at.i'll just show you that in an

example of that in bladdercancer. you might have an initial stagehere which is called ta. t is the tumor rating,t for tumor. this is a very small tumorthat's just confined to the lining.when it gets larger it's classified as t1.when it gets up to stage t2 it's starting to invade from thelining of the bladder into the other tissues of the bladder,t3, t4. by the time it's got to staget4, it's occupying not only the

whole thickness of the wall ofthe bladder but it's started to invade other tissues like theprostate as well. you can see that if youhave a tumor that's at one of these early stages,local therapy might work; surgery or radiation,or local chemotherapy which we'll talk about.as it begins to invade other organs, then it becomes moredifficult to treat. they can spread and i don'tmean for you to--tumors can spread, and i don't mean for youto be able to see all this here

but you can look at this,these slides will be posted as usual.not only can you classify the normal--the original site of thetumor and that's classifications of melanoma from t1 up to t4 andthey're defined here, but you can classify whether ithas spread locally to lymph nodes.that's these end stages here, and whether it has metastasizedto different sites. ordinarily, a physician willclassify a tumor according to the tumor nodal involvementmetastasis classification that's

appropriate for that kind oftumor. this allows physicians tosay exactly where your cancer is at in development.we know, because we've been treating cancer for a long timenow, you can select a treatment that's most likely to work forthe stage that it's at. this, all to say thatdiagnosing specifically where a cancer is at in its developmentwithin a patient is very important for deciding what kindof a treatment is likely to lead to a good outcome.one of the things that

biomedical engineers have workedvery diligently on over the last 50 years or so is designing newmethods for cancer diagnosis. we've talked about some ofthese as we've gone through the course and i just want tohighlight them here. we talked about x-rays andusing x-ray radiation to look inside the body.mammography is a special kind of x-ray imaging that's used tolook just at the breasts to see if there are abnormal tissueswithin the breast. this shows a normal mammogramand this shows a mammogram with

some kind of a dense deposithere that's not normal. mammography is used to screenfor breast cancer and it's a very important screen.now women, when they reach a certain age, are recommended tohave mammography a certain number of times per year or perdecade just to try to detect cancers at an early stage.this is an example of biomedical engineering fordiagnosis. pap smears also done duringroutine pelvic exams in women, where a swab is used to removesome cells from the cervical

region.then you can look at these cells under the microscope andhere's what a normal pap smear would look like.you can see the cells are flat, they have small nuclei,not a lot of protein and so the cells don't stain very darkly.malignant cells, on the other hand,cells that indicate there might be cancer present have largernuclei, more intense staining, abnormal shapes.so, someone who looks at cells from cervical pap smears all thetime can quickly tell if there's

the danger that there might be atumor growing within a patient who's had a smear like this.now, this requires a visit to the office and a procedure;wouldn't it be nice if there were blood tests that you coulddo for cancer? of all the technologies wetalked about; we talked about elisa's forexample and all the ways that we can look into the blood to tryto see what chemicals are present there.if you could find chemical signatures of cancer that couldbe detected in blood,

or in urine,or in some other fluid from the body, that would be a greatthing. unfortunately,there aren't too many examples of that yet.we don't know how to do that very well.we do know for prostate cancer and for certain other kinds ofcancers there are molecules that you can detect in the blood.in prostate cancer there's a very particular molecule calledprostate specific antigen, psa.if the levels of psa rise in

your blood, that's a sign thatthere's something going wrong in your prostate and you get a morethorough exam. blood tests are available butonly for certain kinds of cancers and they're not widelyavailable yet, although we would like for themto be. if you have a high--ifyou're a male and you have an abnormally high prostatespecific antigen level in your blood,you might get a more thorough examination and you mightuse--and your physician might

use an approach like ultrasoundguided biopsy. here, if you can see in thisdiagram here, this is a much less pleasantexperience then a blood test but there's a device that's insertedthrough the rectum up to close to where the prostate is.this device has an ultrasound probe on it.you can look by ultrasound into this region of the body,identify where the prostate is, and even where a growth on theprostate might be and then a needle comes out from thisdevice and takes a small sample

of tissue.this tissue is then taken to the laboratory and looked at inthe same way that a pap smear might be looked at.we talked about using optical microscopy or usingoptical instruments to probe inside the body into cavitiesthat we can't see. there's lots of technologyavailable for this now, including sigmoidoscopes andcolonoscopes, which are fiber optic systemsthat can be inserted into the colon.can be--if they're designed

properly, inserted very far upinto the colon to actually let you look through a lens atwhat's happening on the surface of the tissue.this has been a very important advance in terms of identifyingcancer of the colon, for example.similar scopes are available to look in the lung for lung cancerand to look in a variety of other sites in the body to lookfor cancer and other diseases. a lot of engineering technologyhas been brought to bear on the problem of diagnosing cancer anddiagnosing cancer early.

what do you do if a canceris present? well the--arguably the oldestform of cancer therapy is surgery.surgery is used for biopsy to take small samples to see if agrowth, for example, is abnormal.if you have an abnormal growth on your skin,the surgeon might cut off some of that tissue and send it to alaboratory for analysis and to find out if it's cancer or not.also used for looking deeper in the body, surgery is.surgery is used for prevention

of cancer.if you have abnormal growths called polyps in the colon,a surgeon can remove those polyps and prevent them fromprogressing into a more serious disease.polyps on their own aren't necessarily cancerous but theycan develop into cancer, there's an association withthat. so, why not remove themsurgically before they have the chance?surgeries often remove--used to remove local tumors in the lung,in the brain,

the colon, the prostate,so surgery is a well established form of cancertreatment. radiation can also be usedto treat cancer. this relates to the subject ofimaging that we talked about several weeks ago.we talked about using electromagnetic radiationbecause it can penetrate into the body and using that to takepictures of what's inside. but we also talked about formsof radiation that had biological effects.we talked about ionizing

radiation, for example,and ionizing radiation can cause changes in the body.this is radiation that's on the high frequency,short wavelength end of the electromagnetic spectrum.so, x-rays or gamma rays, high frequency,small wavelength. they can penetrate throughtissues very easily and they can interact with atoms and nucleiinside of the molecules inside your body.ionizing radiation, these forms of high energyradiation have biological

effects.we talked about one of those effects is that they can causethe ejection or the deviation of electrons on atoms within theskin. these change,these ionizations that occur as a electrons are ejected fromatoms within the skin, can cause cell damage.this kind of ionization is happening all the time.you go out in the sun and radiation impinges on your skin,it causes some damage. there are forms of ionizingradiation present at low levels

in the environment around us,.ordinarily that causes no problem because the cells inyour body are able to repair damage.you have repair mechanisms, either by producing new cellsor by repairing the dna that gets damaged in cells,you can recover from the damage that happens.but if radiation continues to be delivered to that tissue,you can overwhelm the body's ability to repair itself.you can actually cause sections of tissues or cells withinsections of tissues to die,

and that's the basis forradiation therapy. this graph which is--whichdescribes an experiment that was done many decades ago,shows how radiation can be used to kill cells.this axis here shows a dose of radiation that's delivered tocells in culture. radiation is focused on a petridish that contains cells and then you expose them to someamount of radiation. the dose of radiation is goingup as you move this way. then, you look to see how manycells survived that procedure,

how many cells survived thisdose of radiation. let's look at a dose of 6 gyhere, gy is a radiation unit called the gray.at this dose of gy's, if you move up this scale here,you'll kill all but .001 fraction or .1% of bone marrowcells. you would kill most of the bonemarrow cells that were exposed by radiation of this kind.you would kill about 90% of cells from the breast,and you would kill even less of these other kinds of cells here.that illustrates another

point, that cells have differentsensitivities to radiation. if you know something about thetype of cells you're trying to treat by radiation,then you can adjust the dose that you give so you're killingonly the ones that you want. some cells are always going tobe susceptible. cells of the bone marrow,for example, very susceptible to radiation.how do you avoid that problem? that you want to kill cells ofthe tumor but you don't want to kill cells that are alsosensitive to radiation in other

parts of the body?you do that by just focusing the radiation on the site thatyou want. you do it by localizing wherethe radiation is delivered. so, biomedical engineersand physicists have developed methods for external beamradiation. these are devices that looksomewhat like the imaging systems we talked about severalweeks ago. they're delivering high dosesof ionizing radiation and you can see that perhaps that thisthing is on a cradle that swings

back and forth,and there are lenses in here to focus the radiation.the physician can move it to whatever site that he wants inthree dimensions and focus the beam so it hits only the tissuethat you want to expose to radiation.these techniques depend very much on computers and onmathematical models of what the tissue looks like inside yourbody, they're guided by imagingmethods, but the idea is to deliver only radiation at thesite that you want too.

can you do a perfect job?no, but you can do a pretty good job in focusing theradiation at the site that you want.this is described a little bit more in the chapter in yourbook. another way to getradiation delivered only where you want is to put the radiationsource inside the body in the location you want and that'scalled brachytherapy. this is an example of aprostate tumor that's filled with what looked like littlestars, or little bright dots.

each one of these bright dotsis a small metal seed that's filled with a radioactivematerial. those are implanted physicallyin the tissue, and then the tissue around itis exposed to radiation. it's a special kind ofradiation that only penetrates a certain depth in the tissue.as it penetrates, it delivers ionizing radiationto all the cells around it. you can see these small seedsare arrayed throughout the tissue so that you can treat itas uniformally as possible.

so, radiation can be used totreat tumors. another thing i wanted toshow you on this slide here is that some cells can be made tobe more sensitive to radiation and they ordinarily are.that example is shown here with these human cells that havebeen--well, that they lack the normal dna repair mechanisms.cells that lack dna repair mechanisms, if you expose themto ionizing radiation; they're much more sensitivebecause they don't have the mechanisms to repair sub-lethaldamage.

one important area of researchis trying to find drugs that you can deliver that will accumulatein tumor tissue to make them more sensitive to radiation,which you then deliver in the ways that i've described.there are a variety of different approaches that areunder study here for delivering radiation more carefully,more selectively, to specific regions of thebody, and to design drugs or other strategies to make tumorsmore sensitive to the radiation you deliver.you know about chemotherapy.

again, this is a slide that idon't intend for you to be able to read on your--in yourleisure, you can look at the slide whenit's posted and just gives you some idea of the breadth ofknowledge that we now have about chemotherapy drugs.there are many different classes of drugs that have beendeveloped and studied and employed for treating cancer.most of these drugs work in a similar fashion,by interfering with dna, or by interfering with themechanisms by which cells repair

dna so that you can halt cellgrowth. if you crosslink all the dnainside of a cell it can't synthesize any more dna.then, it can't divide and proliferate and that's the basisof action for many of these, although not all,so i'll let you look at those at your leisure.one of the problems with chemotherapy is that these drugshave effect not only on tumor cells but they have effects onnormal cells. if you deliver chemotherapythroughout the body,

not only do you have an effecton the tumor, an effect that you want,but you have an effect on other tissues.in particular, the kinds of tissues where cellgrowth, controlled cell growth is an important part of theirphysiology; the intestine,the bone marrow, your hair, skin.patients who have chemotherapy often get digestive problems,severe digestive problems. t hey get anemia,or infections because they're

not producing cells in theirbone marrow anymore. they lose their hair becausehair is produced by cells that are dividing,in the skin. they get rashes and other skinsymptoms because their skin isn't repairing and remodelingin the normal way, you know this.one concept that has emerged over the last 10 yearsor so is to deliver chemotherapy drugs locally instead ofdelivering them over the whole body.i gave you this example from my

own research lab a few weeks agowhen we were talking about drug delivery.just to remind you, here's a situation wherethere's a tumor in the brain. this can be treated by surgery,and in this case the surgeons were given drug deliverysystems. these were degradable polymerwafers that were filled with high concentrations ofchemotherapy. in the operating room,after they removed the tumor, they can place these drugdelivery systems in the brain.

the patient leaves theoperating room with most of the tumor removed,and with high dose chemotherapy delivered locally over a longperiod of time after they leave the operating room.this should remind you of the brachytherapy we talked about afew slides ago. instead of depositing a dose ofradiation in here, we deposited a dose of drugs.deposited it in a way that these drugs could be releasedslowly over time, and hopefully locally kill anyresidual tumor cells that are

remaining.one of the most impressive, important and exciting newdevelopments over the last 5 years has been the developmentof new chemotherapy agents that work by mechanisms of actionthat were not known previously. this is an example of modernbiology and our understanding of cancer biology,in particular, leading to the design of drugsthat are more specific to cancers,because they take advantage of mechanisms that only cancercells typically use.

one of those is a drug calledgleevec. remember in the 4^(th) week ofthe class we talked about cell communication.we talked about signal transduction and how messagesget from the outside of a cell into the inside of a cell.we talked about how important a class of signaling moleculescalled tyrosine kinases were to creating intracellular signals.well, it turns out that certain kinds of tumors you usea special tyrosine kinase called bcrabl and that that tyrosinekinase can be inhibited by a

drug that was designed toinhibit it, called gleevec.now, this is one of the first examples of what's calledrational drug design, in that biologists haveidentified this particular tyrosine kinase.they knew it was involved in signaling inside certain kindsof cancers, in particular, a certain kind of lymphoma.they studied this molecule in its molecular detail anddeveloped a drug, now called gleevec,that would interfere with the

action of that molecule.interfere only with the action of that molecule and not all theother tyrosine kinases that are important for healthy cell lifein the rest of your body. this drug prevents kinaseactivity; it does it by blocking thebinding site for atp. remember that atp was a secondmessenger that kinases use in order to phosphorylate protein.this is an exciting example because it's the first--one ofthe first examples of rational design of a drug at a veryspecific molecular target inside

tumors.now, unfortunately, it's limited.gleevec is limited in its use to only a couple of subclassesof tumors that express this tyrosine kinase at highconcentrations, but i think the idea of it isone that can be translated outside.another new drug that's been developed in the last twoyears is called herceptin. now, herceptin is unique in anumber of different ways. one is that it's an antibody,and we talked about the role of

antibodies in the immuneresponse several weeks ago. we talked about how vaccinesare often designed in order to get your body to produceantibodies to an infectious disease.so, you're familiar with the concept of using antibodies toneutralize pathogens. here's an antibody that wasdesigned to bind to a receptor that appears only on cells inbreast cancer. this receptor is called her2;it's a form of a growth factor receptor that is particularlyhighly expressed in some kinds

of breast cancers.if you deliver this molecule herceptin,it's an antibody which binds to this receptor and prevents itsnormal function. its normal function is tosignal breast cancer cells to grow.when this antibody binds, it shuts off that growth signalthat the breast tumor cell is getting from this receptor.it also promotes the immune response to the tumor.you can imagine if this is a breast cancer cell that has lotsof these receptor molecules on

the surface and now you put inan antibody, you deliver an antibody whichgets coated on the surface, now this surface istagged--this cell is tagged for recognition by your immunesystem. the immune system can develop aresponse to this tumor as well. these are both exciting newpotential therapies for cancer. they're real therapies for somecancer, but point the way towards more broadly applicablemethods that might be used to designing chemotherapy agents.the problem is that it takes a

long time and a lot of money,and a lot of effort in order to get from the point where youdesign a new chemotherapy drug to the point where it can beused in patients. i thought i would end thislecture by just reviewing a little bit about that processand try to get you a sense for why,in practical terms, there haven't been more drugsdeveloped for cancer over the past several decades.the process occurs in steps and i'm going to look at it overa time scale of about 20 years

here.it involves both testing in vitro, testing in test tubesin the laboratory. testing, often in cellcultures, to look for drugs that have properties that you thinkmight make them useful cancer. usually from the time that youthink about a drug, i have a drug,say drug x and i think it might inhibit this signaling pathwayin colon cancer. so, what do i do first?i get some colon cancer cells, i expose it to the drug,i see if it works in culture.

this is all called thediscovery phase. the next stage i might do if ifind that my drug works well in cultured cells and i'm startingto uncover the molecular mechanisms and how it works,is test it in animals. i might take animals that havecolon cancer and try to treat them with a drug.this is still in discovery and this is a phase that--calledanimal testing. now, you begin to refineyour approach. you begin to refine yourapproach such that you're

starting to test not only forthe activity in animals because you find that,'yes, your drug x does--is an effective treatment for cancer.'you trying to think about what's the optimal dose,how much dose would i need if this worked the same way inpeople. you start testing differentaspects of it in animals in preparation for testing inpeople. that's called,that first step in vitro is called lead discovery.my lead drug is x,

this is a promising lead thati'm following, and in animal testing you dolead optimization. all of this takes a long time,could take 4 years from the point that you think,'maybe this drug is good,' to, 'yes i've shown that really iseffective in animals.' then, a process of clinicaltesting happens, and the clinical testing occursin phases. in order to do testingclinically, you have to be approved by the government to dothat.

in this country an organizationcalled the food and drug administration,the fda, is the only one that can giveyou approval to take--to test an experimental medicine in people.they do that because you file an application called an ind orinvestigational new drug application.they look at all the data you've collected over the lastfour years and they say, 'yes you've convinced us thatthis looks like a good drug, it looks like it'll be safe,you can go ahead and start

testing it in people.'you first do small studies, you deliver to a few people,usually not people that have disease, but people that don'thave disease. you deliver it in small dosesand you slowly increase the amount of dose that you givethem. what you're looking for here isnot effectiveness of the drug but you're looking for safety.is it safe? what dose do i begin to seeside effects? this allows you to narrow inthe range that you're going to

use in people to test this drugfor its effectiveness, that's called phase i.phase ii, you start to look in patients that have the diseasein a small number of patients, to just look to see if the drugis effective or not. phase i, you're asking whetherit's safe, in phase ii you're asking if it's effective in thepatients that you would like to use it in.you do that in a small number of patients first just becausethis is the first time it's been used to test effectiveness inpeople and you're not quite sure

what's going to happen.so, you do it in a small number of patients just to show that itworks the way that you want. if it does work the way youwant you start phase iii which is a very large clinical studythat is in the number of patients you need to show thatit is effective at treating the kind of cancer you want.how many patients are involved in studies like this?well, it could be hundreds, could be thousands.depends on the disease, how prevalent the disease is,what the normal course of the

disease is,and how many patients you need to look at in order to beabsolutely sure that you saw an effect that wasn't just due tochance. these are very complicatedstudies to do, and hence very expensive.remember when we were talking about vaccines,we talked about a phase iii study of the polio vaccine thatwas invented by jonas salk. how many patients were involvedin that clinical study, does anybody remember?how many patients were involved

in that phase iii clinical studyof the polio vaccine? who could remember that?i remember; 1.8 million eight year oldswere involved in that study, so clinical studies can behuge. in the case of an infectiousdisease, it's particularly a large number because you need todeliver it to enough people to see--a vaccine,to see that you've changed the incidence of disease within apopulation. in cancer trials,they tend to be hundreds or

thousands in size.if this phase iii trial works then you're allowed tosell the drug. the fda gives you permission tosell the drug, and for physicians to prescribeit. the study doesn't end there,in that all manufacturers of drugs are required to keep trackof what happens as their drug is introduced into the population.this is called phase iv, as physicians start using it totreat cancer they're required to look at how these things work.you will have noticed,

in the newspaper over the pastfew years, some very famous drugs that turned out to haveside effects that weren't expected after they werereleased into the general population.once it starts being used by physicians all over the countryin many, many more patients sometimes rare side effectsappear that we didn't expect before.so, one continues to do research and study even afterthat. the challenge for drugcompanies is that this takes a

very long time,it takes a lot of money. there's lots of places whereyour drug can fail. my drug x, which i described asgoing neatly through in vitro studies,animal testing, clinical testing might havestopped working at some stage. i might have found some problemwith its safety when i started testing it in human volunteers.i might have found that it didn't work as well in animalsas i expected it too based on in vitro studies.people estimate that for every

10,000 compounds,10,000 x's that are thought of in laboratories,only one of them eventually gets approved by the fda.this is why drug development costs so much money in thiscountry, because you have to look at a lot of compounds andtest them pretty extensively to find the one that's reallyuseful for treating disease. i don't think we want tochange that, because this process of fda approval wasintroduced early in this century when people were selling drugsout of the back of covered

wagons and moving from town totown. they're called snake oilsalesmen or other things. people could sell anything theywanted and claimed that it treated a disease.now, we have a very highly refined system for asking peoplethat are going to sell drugs to prove that they work,but that system costs a lot of money.there are opportunities, i think, for biomedicalengineers to improve how this works by designing bettermethods for in vitro

study.by using techniques we talked about, like in cell cultureearly on, to use those techniques more efficiently,to discover and test properties of drugs.so, this is going to be an area where i think there is lots ofgrowth and opportunities in the future.just in closing, i just put this website upthere; it's from science magazinewhich is a very high-profile scientific journal.they published a poster which

is available online that talksabout sort of modern developments in cancer diagnosisand treatment. i put a few sort of snapshotsfrom that poster into the power point presentation which will beavailable. i encourage you to go to thiswebsite and look at this information.you can find out more about what are the sort of excitingpathways for the future in biomedical engineering andcancer treatment. great, so i'll see you onthursday.