BENG 100: Frontiers of Biomedical Engineering

Lecture 24

 - Biomedical Engineers and Cancer


Professor Saltzman uses cancer diagnosis and treatment as an example to demonstrate the some applications of biomedical engineering technologies and methods. Some issues involved in cancer treatment, such as tumor angiogenesis, radiation sensitivity, drug localization, and cancer stem cells are mentioned. Next, he describes the phases (I-IV), in compliance to guidelines enforced by the Food and Drug Administration (FDA), which a new drug compound must go through to gain approval prior to public distribution/sale. Finally, Professor Saltzman draws attention to the areas that biomedical engineers may contribute to, to improve this process.

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Frontiers of Biomedical Engineering

BENG 100 - Lecture 24 - Biomedical Engineers and Cancer

Chapter 1. Introduction to Cancer [00:00:00]

Professor Mark Saltzman: So, what I’m going to talk about today and Thursday is two topics, which what I hope to do is sort of bring together some of the information that we’ve been talking about over the course of the term. To do that, I want to focus on two areas, today talk about cancer–a big subject, and so we’ll just scratch the surface. The main point that I want to make is how some of the technologies that we’ve been talking about over the course of the term are having an impact on cancer diagnosis and care, and to sort of point to some areas where they’ll likely be more progress and opportunities for progress in the future. Then, on Thursday, we’ll do the same thing but talking about the subject of artificial organs. One that we’ve brushed on a couple of times through the semester, but just try to spend some focus time on it on Thursday. Section meeting on Thursday afternoon, we’ll do a course review. I’ll be there for each of the sections. I’ll just be leading a discussion about what we’ve covered in the course and what kinds of things will be on the final. Any questions?

You know what’s described here on this slide, that cancer is a deadly and, unfortunately, not uncommon disease. These are some statistics from 2006 collected by The American Cancer Society. One of the things that we do fairly well as a nation, now, is keep track of cancer cases and progress. This has been an important part of 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 effort to 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 on research for cancer.

This just summarizes some of that information. For 2006, new cases of cancer you can see over a million new cases, deaths from cancer about half 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 of deaths that are caused by cancer and if you want to learn more about sort of that, I urge you to go to The American Cancer Society website which is listed here.

Just a few facts about cancer that you probably know something about this, it’s now the most common cause of death in the U.S. and that’s true in many developed countries. Cancer and heart disease have been neck and neck in terms of the number one cause of deaths in developed countries for many years now. It looks like cancer is winning and we’ll talk about that in a minute. Cancer’s caused by mutations in genes that control cell growth. You know that a cancer or formation of a tumor is an unwanted or uncontrolled growth of cells. Cell division runs amuck and cells don’t stop dividing under circumstances where they’re supposed to. So, you get–a mass is formed and that mass is–it represents the unwanted growth of cells.

Chapter 2. Cancer Epidemiology and Biology [00:03:56]

The mutations that cause cancer, that cause these defects in cell growth, can be either inherited or environmental. We know that there are thing in the environment that cause cancer, some viruses can cause cancers. One of the clearest links is between human papillomavirus, a sexually transmitted disease and cervical cancer in women. There is a new vaccine for HPV, human papillomavirus and it’s expected that this vaccine which will prevent spread of the virus will also significantly reduce cancer cases. Other kinds of viruses are linked to liver cancers, for example. Chemicals can also, in the environment, can also cause cancer, and we’ll talk more about that in a minute. Most cancers also involve some genetic 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 basis for 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 impressive number. The age adjusted mortality rate for cancer is about the same in the 21st century as it was 50 years ago, that is, the rate of death from cancer hasn’t changed very much in the last 50 years. This, in spite of the fact that there’s been a lot of attention to cancer and learning more about cancer, and its causes, the basic biology and in trying to 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 in others. This just, I think, reflects the fact that both cancer is a heterogeneous disease. You know that it occurs in a variety of sites throughout the body, but in each of those sites cancers can be quite different. It’s not one disease but its family of diseases. Because of that, it’s been hard to make progress in treatment because all of them have slightly different characteristics.

This just illustrates that last point a little more clearly. Change in U.S. death rates by cause from 1950 to 2003, so over that period deaths from heart disease went down dramatically. Deaths from cerebral vascular diseases, so deaths of the circulatory system in the brain, so this is mainly stroke and aneurisms down dramatically. Deaths from infectious diseases, we talked about vaccines several weeks ago which has a big impact on mortality from infectious diseases, also down over that years. Deaths from cancer stay about the same. While we’ve made great progress, we’re not yet at the point where we’re changing the outcomes from cancer very dramatically.

I mentioned a few minutes ago that exposure to chemicals can cause cancer, and you know this. One of the most well known exposures that’s clearly a cause of cancer is tobacco use. This is tobacco use mainly thinking about cigarette smoking, but the same thing could be true of any kind of tobacco use. Smoking in other–cigars or chewing tobacco also causes cancer because the chemicals in cigarette smoke or in tobacco, in particular. Some of the tars that are associated with smoking cause cancer of the lung in particular.

This was first noticed by looking at epidemiological data. We talked about public health and epidemiology a few weeks ago where you look at how diseases appear in populations and you try to figure out why things are changing. Here’s as cigarettes were consumed more in the U.S., you can see the trend in cigarette 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 that is because cigarette smoking was initially more popular among men than among women, but advertising and the women’s movement changed that.

Cigarette smoking became something 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 in some 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 yet happened in women. Evidence first came from epidemiology but then after it was realized that there was an association between cigarettes smoking and cancer. Then, you can start to look more closely and try to figure out what the molecular cause of it is.

We now know quite a lot about how the chemicals in smoke cause these sorts of malignant transformations in cells that lead 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 to death, and in both men and women, lunch cancer is number one. After that it changes the top three in men being lung, colon and prostate; in women lung, breast and colon and accounting for just those top three, the large majority of cancers. Cancer of the pancreas is much less common but because it’s so difficult to detect and we’ll talk about methods of detection. The pancreas is an organ that’s deep within your body and it’s hard to find when things are going wrong with it. Because it’s difficult to detect cancer of the pancreas it very frequently leads to death, and of course this is in the news now because this is the kind of cancer that Patrick Swayze has. Life expectancy when you have pancreatic cancer is–life expectancy is very low because it’s usually in an advanced stage when it’s discovered.

Cancer cells are different, so what makes all these cancers at different sites similar is the similar characteristics that the cells that form cancers have. I mentioned already that one of the things that characterizes cancer is that cells divide abnormally. They divide, usually, more rapidly. We talked about, several weeks ago when we were talking about cell culture, we talked about cells that you would isolate from tissue and they would grow at a rate of about by doubling their number everyday if you maintained them in culture. Cancer cells can grow much faster than that so they have mechanisms for dividing very rapidly.

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 and reproducing within your body. Cells in you intestinal tract for example, cells in the liver, cells in the kidney continually dividing, cells in your skin. But ordinarily your skin stays the same size that it is because are cells are dividing but they know when to stop. They stop when they reach the right density, the right shape, they know where they’re supposed to be. Cancer cells don’t, they continue to divide even when they get signals that they’re supposed to stop dividing. Because of this tumors form, abnormal growths–the organ of–origin becomes larger than it ordinarily would.

They generally don’t respond to signals that are provided by neighboring cells, we talked about cell communication and how important that 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 cells that are communicating in the right way. There’s a loss of that normal molecular communication when you have cancer. They don’t differentiate normally but tend to remain as immature de-differentiated or undifferentiated cells.

What’s this like? This is like we talked about stem cells, stem cells are less mature than differentiated tissue cells. They grow rapidly; both stem cells which self-renew and cancer cells. They don’t form mature types of cells and there’s a lot of linkages know known between stem cells and cancer. Some people think that within any individual tumor, there are cancer stem cells that really are the most important ones to treat. If you get rid of even the bulk of cancer cells without getting rid of these very stem like cells in cancers the tumors will regrow again.

So, normal differentiation like stem cells is a problem with cancer cells. They don’t adhere readily to other cells and extracellular matrix, they do not become specialized and die. Because cells in your skin are continually going through not just birth, not just growth of new cells but death. There’s skin cells that are dying and being shed from your body all the time. Cancer cells don’t undergo those normal processes of cell death that lead to regulation of tissue structure.

If a cancer forms, it tends to go through different stages and that this cell, for example, in this tissue is a pre-malignant cell. If it becomes malignant, it will start dividing and growing out of control and you can see that here. That tumor that forms at the initial site or the site of the origin of a cancer is called the primary tumor. These tumors, if they grew, would ordinarily stop at a size of 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’t get nutrients, oxygen, glucose, the things that the cell needs, amino acids.

The things that it needs in order to produce new cells can’t get in because those are normally provided by the bloodstream. When the cell is just dividing out 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 fact that cancers at this stage, as they move from this primary stage to invasive cancer, they develop an ability to stimulate the growth of blood vessels So, now you can see blood vessels are growing into and through this tumor, they develop their own blood supply. They’re able to get nutrients readily, and this is when the growth of the tumor really starts to take off. We’ll talk about some therapies that block this process of new tumor growth called angiogenesis. Many people think if you could block that process selectively in tumors then you could halt all tumors to a very small size that would not cause problems.

An additional stage after angiogenesis that some tumors can go through is a process called metastasis. That’s where tumor cells actually leave their site of origin and travel to other places in the body. That’s shown schematically in this cartoon here. A tumor cell entering the circulation, it can flow through the circulation, and maybe get lodged at some distant site and begin the process of tumor formation at that distant site. This is obviously a bad thing because maybe you can treat the primary tumor in a variety of different ways which we’ll talk about in just a minute. Once it begins to spread throughout the body becomes much more difficult to treat. You have not just one tumor, but potentially hundreds or thousands of tumors that are forming throughout the body.

Chapter 3. Detection of Cancer [00:16:25]

The treatment for tumors–for cancer–depends very much on what stage it’s at when it’s identified. For every kind of cancer physicians, oncologists, have developed classification methods 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 bladder cancer. You might have an initial stage here which is called TA. T is the tumor rating, T for tumor. This is a very small tumor that’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 the lining of the bladder into the other tissues of the bladder, T3, T4. By the time it’s got to stage T4, it’s occupying not only the whole thickness of the wall of the bladder but it’s started to invade other tissues like the prostate as well.

You can see that if you have 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 more difficult to treat. They can spread and I don’t mean for you to–tumors can spread, and I don’t mean for you to 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 the tumor and that’s classifications of melanoma from T1 up to T4 and they’re defined here, but you can classify whether it has spread locally to lymph nodes. That’s these end stages here, and whether it has metastasized to different sites. Ordinarily, a physician will classify a tumor according to the tumor nodal involvement metastasis classification that’s appropriate for that kind of tumor.

This allows physicians to say exactly where your cancer is at in development. We know, because we’ve been treating cancer for a long time now, you can select a treatment that’s most likely to work for the stage that it’s at. This, all to say that diagnosing specifically where a cancer is at in its development within a patient is very important for deciding what kind of a treatment is likely to lead to a good outcome. One of the things that biomedical engineers have worked very diligently on over the last 50 years or so is designing new methods for cancer diagnosis. We’ve talked about some of these as we’ve gone through the course and I just want to highlight them here.

We talked about X-rays and using X-ray radiation to look inside the body. Mammography is a special kind of X-ray imaging that’s used to look just at the breasts to see if there are abnormal tissues within the breast. This shows a normal mammogram and this shows a mammogram with some kind of a dense deposit here that’s not normal. Mammography is used to screen for breast cancer and it’s a very important screen. Now women, when they reach a certain age, are recommended to have mammography a certain number of times per year or per decade just to try to detect cancers at an early stage. This is an example of biomedical engineering for diagnosis.

Pap smears also done during routine pelvic exams in women, where a swab is used to remove some cells from the cervical region. Then you can look at these cells under the microscope and here’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 larger nuclei, more intense staining, abnormal shapes. So, someone who looks at cells from cervical Pap smears all the time can quickly tell if there’s the danger that there might be a tumor 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 could do for cancer? Of all the technologies we talked about; we talked about ELISA’s for example and all the ways that we can look into the blood to try to see what chemicals are present there. If you could find chemical signatures of cancer that could be detected in blood, or in urine, or in some other fluid from the body, that would be a great thing. 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 of cancers there are molecules that you can detect in the blood. In prostate cancer there’s a very particular molecule called prostate specific antigen, PSA. If the levels of PSA rise in your blood, that’s a sign that there’s something going wrong in your prostate and you get a more thorough exam. Blood tests are available but only for certain kinds of cancers and they’re not widely available yet, although we would like for them to be.

If you have a high–if you’re a male and you have an abnormally high prostate specific antigen level in your blood, you might get a more thorough examination and you might use–and your physician might use an approach like ultrasound guided biopsy. Here, if you can see in this diagram here, this is a much less pleasant experience then a blood test but there’s a device that’s inserted through 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 the prostate might be and then a needle comes out from this device and takes a small sample of tissue. This tissue is then taken to the laboratory and looked at in the same way that a Pap smear might be looked at.

We talked about using optical microscopy or using optical instruments to probe inside the body into cavities that we can’t see. There’s lots of technology available for this now, including sigmoidoscopes and colonoscopes, which are fiber optic systems that can be inserted into the colon. Can be–if they’re designed properly, inserted very far up into the colon to actually let you look through a lens at what’s happening on the surface of the tissue. This has been a very important advance in terms of identifying cancer of the colon, for example. Similar scopes are available to look in the lung for lung cancer and to look in a variety of other sites in the body to look for cancer and other diseases. A lot of engineering technology has been brought to bear on the problem of diagnosing cancer and diagnosing cancer early.

Chapter 4. Cancer Treatment Options [00:23:45]

What do you do if a cancer is present? Well the–arguably the oldest form of cancer therapy is surgery. Surgery is used for biopsy to take small samples to see if a growth, 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 a laboratory 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 from progressing into a more serious disease. Polyps on their own aren’t necessarily cancerous but they can develop into cancer, there’s an association with that. So, why not remove them surgically 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 cancer treatment.

Radiation can also be used to treat cancer. This relates to the subject of imaging that we talked about several weeks ago. We talked about using electromagnetic radiation because it can penetrate into the body and using that to take pictures of what’s inside. But we also talked about forms of 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 through tissues very easily and they can interact with atoms and nuclei inside of the molecules inside your body.

Ionizing radiation, these forms of high energy radiation have biological effects. We talked about one of those effects is that they can cause the ejection or the deviation of electrons on atoms within the skin. These change, these ionizations that occur as a electrons are ejected from atoms 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 ionizing radiation present at low levels in the environment around us,. Ordinarily that causes no problem because the cells in your body are able to repair damage. You have repair mechanisms, either by producing new cells or 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 within sections of tissues to die, and that’s the basis for radiation therapy.

This graph which is–which describes 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 to cells in culture. Radiation is focused on a Petri dish that contains cells and then you expose them to some amount of radiation. The dose of radiation is going up as you move this way. Then, you look to see how many cells survived that procedure, how many cells survived this dose of radiation. Let’s look at a dose of 6 Gy here, 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 marrow cells. You would kill most of the bone marrow 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 different sensitivities to radiation. If you know something about the type of cells you’re trying to treat by radiation, then you can adjust the dose that you give so you’re killing only the ones that you want. Some cells are always going to be susceptible. Cells of the bone marrow, for example, very susceptible to radiation. How do you avoid that problem? That you want to kill cells of the tumor but you don’t want to kill cells that are also sensitive to radiation in other parts of the body? You do that by just focusing the radiation on the site that you want. You do it by localizing where the radiation is delivered.

So, biomedical engineers and physicists have developed methods for external beam radiation. These are devices that look somewhat like the imaging systems we talked about several weeks ago. They’re delivering high doses of ionizing radiation and you can see that perhaps that this thing 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 in three dimensions and focus the beam so it hits only the tissue that you want to expose to radiation. These techniques depend very much on computers and on mathematical models of what the tissue looks like inside your body, they’re guided by imaging methods, but the idea is to deliver only radiation at the site that you want too. Can you do a perfect job? No, but you can do a pretty good job in focusing the radiation at the site that you want. This is described a little bit more in the chapter in your book.

Another way to get radiation delivered only where you want is to put the radiation source inside the body in the location you want and that’s called Brachytherapy. This is an example of a prostate tumor that’s filled with what looked like little stars, or little bright dots. Each one of these bright dots is a small metal seed that’s filled with a radioactive material. Those are implanted physically in the tissue, and then the tissue around it is exposed to radiation. It’s a special kind of radiation that only penetrates a certain depth in the tissue. As it penetrates, it delivers ionizing radiation to all the cells around it. You can see these small seeds are arrayed throughout the tissue so that you can treat it as uniformally as possible. So, radiation can be used to treat tumors.

Another thing I wanted to show you on this slide here is that some cells can be made to be more sensitive to radiation and they ordinarily are. That example is shown here with these human cells that have been–well, that they lack the normal DNA repair mechanisms. Cells that lack DNA repair mechanisms, if you expose them to ionizing radiation; they’re much more sensitive because they don’t have the mechanisms to repair sub-lethal damage. One important area of research is trying to find drugs that you can deliver that will accumulate in 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 are under study here for delivering radiation more carefully, more selectively, to specific regions of the body, and to design drugs or other strategies to make tumors more sensitive to the radiation you deliver.

You know about chemotherapy. Again, this is a slide that I don’t intend for you to be able to read on your–in your leisure, you can look at the slide when it’s posted and just gives you some idea of the breadth of knowledge that we now have about chemotherapy drugs. There are many different classes of drugs that have been developed and studied and employed for treating cancer. Most of these drugs work in a similar fashion, by interfering with DNA, or by interfering with the mechanisms by which cells repair DNA so that you can halt cell growth. If you crosslink all the DNA inside of a cell it can’t synthesize any more DNA. Then, it can’t divide and proliferate and that’s the basis of 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 drugs have effect not only on tumor cells but they have effects on normal cells. If you deliver chemotherapy throughout the body, not only do you have an effect on the tumor, an effect that you want, but you have an effect on other tissues. In particular, the kinds of tissues where cell growth, controlled cell growth is an important part of their physiology; 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 their bone marrow anymore. They lose their hair because hair is produced by cells that are dividing, in the skin. They get rashes and other skin symptoms because their skin isn’t repairing and remodeling in the normal way, you know this.

One concept that has emerged over the last 10 years or so is to deliver chemotherapy drugs locally instead of delivering them over the whole body. I gave you this example from my own research lab a few weeks ago when we were talking about drug delivery. Just to remind you, here’s a situation where there’s a tumor in the brain. This can be treated by surgery, and in this case the surgeons were given drug delivery systems. These were degradable polymer wafers that were filled with high concentrations of chemotherapy. In the operating room, after they removed the tumor, they can place these drug delivery systems in the brain. The patient leaves the operating room with most of the tumor removed, and with high dose chemotherapy delivered locally over a long period of time after they leave the operating room. This should remind you of the Brachytherapy we talked about a few slides ago. Instead of depositing a dose of radiation in here, we deposited a dose of drugs. Deposited it in a way that these drugs could be released slowly over time, and hopefully locally kill any residual tumor cells that are remaining.

Chapter 5. New Drug Developments in Chemotherapy [00:34:46]

One of the most impressive, important and exciting new developments over the last 5 years has been the development of new chemotherapy agents that work by mechanisms of action that were not known previously. This is an example of modern biology and our understanding of cancer biology, in particular, leading to the design of drugs that are more specific to cancers, because they take advantage of mechanisms that only cancer cells typically use. One of those is a drug called Gleevec. Remember in the 4th week of the class we talked about cell communication. We talked about signal transduction and how messages get from the outside of a cell into the inside of a cell. We talked about how important a class of signaling molecules called tyrosine kinases were to creating intracellular signals.

Well, it turns out that certain kinds of tumors you use a special tyrosine kinase called BCRABL and that that tyrosine kinase can be inhibited by a drug that was designed to inhibit it, called Gleevec. Now, this is one of the first examples of what’s called rational drug design, in that biologists have identified this particular tyrosine kinase. They knew it was involved in signaling inside certain kinds of cancers, in particular, a certain kind of lymphoma. They studied this molecule in its molecular detail and developed 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 the other tyrosine kinases that are important for healthy cell life in the rest of your body.

This drug prevents kinase activity; it does it by blocking the binding site for ATP. Remember that ATP was a second messenger that kinases use in order to phosphorylate protein. This is an exciting example because it’s the first–one of the first examples of rational design of a drug at a very specific molecular target inside tumors. Now, unfortunately, it’s limited. Gleevec is limited in its use to only a couple of subclasses of tumors that express this tyrosine kinase at high concentrations, but I think the idea of it is one that can be translated outside.

Another new drug that’s been developed in the last two years is called Herceptin. Now, Herceptin is unique in a number of different ways. One is that it’s an antibody, and we talked about the role of antibodies in the immune response several weeks ago. We talked about how vaccines are often designed in order to get your body to produce antibodies to an infectious disease. So, you’re familiar with the concept of using antibodies to neutralize pathogens. Here’s an antibody that was designed to bind to a receptor that appears only on cells in breast cancer. This receptor is called HER2; it’s a form of a growth factor receptor that is particularly highly expressed in some kinds of breast cancers.

If you deliver this molecule Herceptin, it’s an antibody which binds to this receptor and prevents its normal function. Its normal function is to signal breast cancer cells to grow. When this antibody binds, it shuts off that growth signal that 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 lots of these receptor molecules on the surface and now you put in an antibody, you deliver an antibody which gets coated on the surface, now this surface is tagged–this cell is tagged for recognition by your immune system. The immune system can develop a response to this tumor as well.

Chapter 6. Technical and Economic Difficulties of Cancer Drug Research [00:38:53]

These are both exciting new potential therapies for cancer. They’re real therapies for some cancer, but point the way towards more broadly applicable methods 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 you design a new chemotherapy drug to the point where it can be used in patients. I thought I would end this lecture by just reviewing a little bit about that process and try to get you a sense for why, in practical terms, there haven’t been more drugs developed for cancer over the past several decades.

The process occurs in steps and I’m going to look at it over a time scale of about 20 years here. It involves both testing in vitro, testing in test tubes in the laboratory. Testing, often in cell cultures, to look for drugs that have properties that you think might make them useful cancer. Usually from the time that you think about a drug, I have a drug, say drug X and I think it might inhibit this signaling pathway in 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 the discovery phase. The next stage I might do if I find that my drug works well in cultured cells and I’m starting to uncover the molecular mechanisms and how it works, is test it in animals. I might take animals that have colon cancer and try to treat them with a drug. This is still in discovery and this is a phase that–called animal testing.

Now, you begin to refine your approach. You begin to refine your approach such that you’re starting to test not only for the 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 in people. You start testing different aspects of it in animals in preparation for testing in people. That’s called, that first step in vitro is called lead discovery. My lead drug is X, this is a promising lead that I’m following, and in animal testing you do lead 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 is effective in animals.’

Then, a process of clinical testing happens, and the clinical testing occurs in phases. In order to do testing clinically, you have to be approved by the government to do that. In this country an organization called the Food and Drug Administration, the FDA, is the only one that can give you approval to take–to test an experimental medicine in people. They do that because you file an application called an IND or Investigational New Drug application. They look at all the data you’ve collected over the last four years and they say, ‘Yes you’ve convinced us that this 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’t have disease. You deliver it in small doses and you slowly increase the amount of dose that you give them. What you’re looking for here is not effectiveness of the drug but you’re looking for safety. Is it safe? What dose do I begin to see side effects? This allows you to narrow in the range that you’re going to use in people to test this drug for its effectiveness, that’s called Phase I. Phase II, you start to look in patients that have the disease in a small number of patients, to just look to see if the drug is effective or not. Phase I, you’re asking whether it’s safe, in Phase II you’re asking if it’s effective in the patients that you would like to use it in. You do that in a small number of patients first just because this is the first time it’s been used to test effectiveness in people 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 it works the way that you want.

If it does work the way you want you start Phase III which is a very large clinical study that is in the number of patients you need to show that it 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 be absolutely sure that you saw an effect that wasn’t just due to chance. These are very complicated studies to do, and hence very expensive.

Remember when we were talking about vaccines, we talked about a Phase III study of the polio vaccine that was invented by Jonas Salk. How many patients were involved in that clinical study, does anybody remember? How many patients were involved in that Phase III clinical study of the polio vaccine? Who could remember that? I remember; 1.8 million eight year olds were involved in that study, so clinical studies can be huge. In the case of an infectious disease, it’s particularly a large number because you need to deliver it to enough people to see–a vaccine, to see that you’ve changed the incidence of disease within a population. In cancer trials, they tend to be hundreds or thousands in size.

If this Phase III trial works then you’re allowed to sell the drug. The FDA gives you permission to sell the drug, and for physicians to prescribe it. The study doesn’t end there, in that all manufacturers of drugs are required to keep track of what happens as their drug is introduced into the population. This is called Phase IV, as physicians start using it to treat cancer they’re required to look at how these things work. You will have noticed, in the newspaper over the past few years, some very famous drugs that turned out to have side effects that weren’t expected after they were released into the general population. Once it starts being used by physicians all over the country in many, many more patients sometimes rare side effects appear that we didn’t expect before. So, one continues to do research and study even after that.

The challenge for drug companies is that this takes a very long time, it takes a lot of money. There’s lots of places where your drug can fail. My drug X, which I described as going neatly through in vitro studies, animal testing, clinical testing might have stopped working at some stage. I might have found some problem with its safety when I started testing it in human volunteers. I might have found that it didn’t work as well in animals as 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 this country, because you have to look at a lot of compounds and test them pretty extensively to find the one that’s really useful for treating disease.

I don’t think we want to change that, because this process of FDA approval was introduced early in this century when people were selling drugs out of the back of covered wagons and moving from town to town. They’re called snake oil salesmen or other things. People could sell anything they wanted and claimed that it treated a disease. Now, we have a very highly refined system for asking people that are going to sell drugs to prove that they work, but that system costs a lot of money. There are opportunities, I think, for biomedical engineers to improve how this works by designing better methods for in vitro study. By using techniques we talked about, like in cell culture early 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 of growth and opportunities in the future.

Just in closing, I just put this website up there; it’s from Science Magazine which is a very high-profile scientific journal. They published a poster which is available online that talks about sort of modern developments in cancer diagnosis and treatment. I put a few sort of snapshots from that poster into the Power Point presentation which will be available. I encourage you to go to this website and look at this information. You can find out more about what are the sort of exciting pathways for the future in biomedical engineering and cancer treatment. Great, so I’ll see you on Thursday.

[end of transcript]

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