Speaker: Jeffrey Boyd

It occurred to me that, given the nature of the presentation that you heard from Birrer earlier and that of which you will hear shortly from Dr. Muller, the best thing that I could do is give a very brief introduction, and reiterate what in my mind is perhaps the major concept that was introduced by Dr. Birrer, and then just lead straight into the next lecture.

Cancer, I think it's very important to recognize in this context of molecular based therapy, what it is and why it should work. This is the reason we think it should work. Cancer is a genetic disease, which is not to say that cancer predisposition is inherited in every case. It is inherited in ovary cancer about 10 percent of the time. But genetic mutations in every case are what drive the process of tumor agenesis. What makes a normal ovarian epithelial cell become a malignant ovarian epithelial cell?

Multiple genes must be mutated in every case. Now, this concept of cancer genetics applies in two ways in the sense of molecular based therapy. DNA, which is the genetic material, the blueprint, for all of the proteins that make cells and tissues and determine the difference between an ovary cell and a brain cell for example, creates RNA that produces protein. This is in its purest form, genetics. Things can go wrong in two ways in this relatively over simplified process.

DNA mutations can occur, which of course result in alterations in the encoded messenger RNA and proteins. These mutant proteins, which drive the cancer process, can thus become targets for therapy. So an altered protein can be targeted in a way that the normal corresponding protein can't, and this is used in many ways in cancer therapy. The other thing that can happen is in the absence of a DNA mutation, abnormal amounts of RNAs and proteins can be made, and this is a frequent occurrence in cancer. Similarly abnormally low amounts of RNAs and proteins can be made with respect to a specific gene and this can also cause problems and this can be targeted in terms of molecular therapeutics.

In terms of specific genetic alterations that we know apply to ovarian cancer, you've already heard a little bit about this. This is just simply a laundry list. What is notable here are two things I think. There are a number of potential candidates in terms of genes, but you also notice that very few of them are mutated or altered in a significantly large fraction of ovarian cancers. So in other words, mutations are rare, Her-b-2 or Her-2 mutations are rare. P53, in the right hand corner, the tumor suppressor gene is probably the most common genetic alteration that we know of in sporadic ovarian cancer. It is a target as you have and will hear shortly.

Finally the last slide I have in this introduction. With all of these targets in ovarian and other cancers there are depressingly few examples of the successful molecular targeting of a particular gene product. Any cancer, never mind ovarian cancer, Herceptin, the Herceptin story with respect to breast cancer and the Gleevec story with respect to CML are the two notable exceptions. So while there is certainly great promise and understanding the molecular genetic alterations responsible for ovarian and other cancers. The reality thus far has been less than we would like, and I think that is in fact at least partially the title of Dr. Muller's lecture on this topic.

Speaker: Carolyn Muller

Good morning. It is a pleasure to be here. I know you all have heard an awful lot this morning about the complexity of ovarian cancer and all these new mechanisms. Well, I know the key of what you want to hear is obviously how can we get this information into something that can help me or my loved ones. How can we use this technology to actually cure cancer, or to help us at least battle the disease. I want to stress to you that we are getting there and, just like anything else, when we first learn about this new paradigm, advances are going to take a little bit of time, and it's going to take very specific means of studying in order to achieve the advances that we want. So, when I thought about how I am going to do this topic, I mean molecular based therapies in ten minutes, I thought, "oh my gosh." There is a lot to say because there is a lot happening. The way I decided to do this talk is to tell it through stories, using a couple of examples, because I wanted to address the questions that I often hear from my patients: "how can I get this treatment?" or "when I go to the web and go to the NCI PDQ site and I see all of these clinical trials, which one should I look for? I can't understand this. Why isn't my institution here? Why is it already closed or it's suspended?" So, I'm hopeful that showing you some of these examples of trial development will help you understand what's happening.

The main goal. If you think about how we treat cancer right now, which is by using a lot of drugs, some of which we have good experiences with, we have seen some improvements on survival. A lot of these drugs were discovered because we smushed up lots of things: trees, plants, stuff that we get from the top of the mountain to the bottom of the oceans, and we find all of a sudden that there is a molecule that can help. Well, molecular therapeutics is a little bit different. In this case, we are actually trying to understand the pathways of cancer first and then use that information to select specific treatments. The smart thing about this approach is that we are trying to target the cancer specifically, not necessarily treatments that affect your whole body, which is in essence what a lot of the chemotherapy is doing. So we want to try obviously to improve survival. This is first and foremost the number one goal. But many of these kinds of treatments may have less toxicity because they are a little more select. These treatments could lead to an improved quality of life, and hopefully in another five to ten years we may actually be able to individualize treatments for your individual cancer. These are the ideas, these are the goals. Sometimes the treatments may be used alone, or sometimes in combination with the drugs we already know. Now I will show you some stories.

The story that I'm going to talk about first is gene therapy, because I think this really does illustrate a lot of the complexity of what happens in therapeutic development. None of these advances happens in a vacuum. We need teams. You've seen this panel of incredibly smart experts up here. Without working together, none of this can happen. You are going to see that with gene therapy. You will also hear about antibody trials, and then I'm going to address very briefly some of the designer drugs.

Gene therapy: As of 2002 there were over 500 clinical trials using gene therapy, of which over 24 of them were designed specifically for ovarian cancer. This illustrates that there are different types of approaches of getting a gene in and different genes to use for different diseases. Now you've heard multiple times from Dr. Birrer and Dr. Boyd that ovarian cancer is a genetic disease. Okay, well you know a little 5-year-old kid could say that, "if it's a bad gene then why don't you just go in a fix the genes." It makes a whole lot of sense. And that is what gene therapy is designed to do. You take the most commonly affected gene that goes bad in ovarian cancer and you try to fix it by putting a good copy of that gene back in the cancer cell. It is difficult to do, because genes are very big molecules and you can't put in a pill and expect them to get absorbed and diffuse into the cancer cells. You have to get very very fancy about how you get these genes in the cells. We use viruses predominantly now but there are some new technologies coming down the pipeline.

So, you take your targeted gene, and for the sake of the argument we are going to talk about the P53 trials, because P53 is broken, or mutated, or doesn't work in about 50 percent to 80 percent of ovarian cancers. Particularly, as the cancers develop drug resistance, P53 often doesn't work. We use viruses: an adenovirus, which is the common cold virus, or you can use a retrovirus also. They both have different capacities for getting the gene into the cancer cells, and they both have different pluses and minuses, which is another whole talk later. Anyway, the first gene therapy trial I'm going to talk about is the BRCA 1 trials. When you talk about BRCA 1, you are often talking about an inherited disease. Many of you in the audience know your BRCA 1 gene status. BRCA 1 is obviously one of the inherited genes that results in a protein that does not function. But BRCA 1 does not function well in other ovarian cancer patients who do not have the inherited mutation. The most remarkable thing about this story is that the gene was cloned and eighteen months later there was a clinical trial. Some people could argue that that was a little too fast, but that shows you the amount of work that had to happen here.

The first trial was a Phase I trial. Nobody knew how to use this stuff. Nobody knew how to use this vector, the retrovirus that carried the BRCA 1 gene. You took the vector and infused it into somebody's belly over several treatments. The initial treatment schema was for five days every twenty-eight days. A lot of testing was done to figure out how this treatment was working both clinically and biologically. So, the patients who entered these trials had a lot of demands that were designed to help with the research in essence, because a lot of information had to be understood from all of the testing done. Outcomes included safety, toxicities, antibody production, and we collected specific information from these women enrolled in the Phase I trial known to have extensive ovarian disease. Twelve patients were treated. Mild fever and peritonitis occurred. There was no significant antibody response in these patients who had a lot of disease, and had been heavily pretreated. BRCA 1 was indeed expressed so the gene actually got in and was produced. There were about two-thirds of the patients who had partial responses or stable disease. So this was great! Everybody got very excited until the Phase II trial when we treated patients with less tumor burden who were perhaps not so immunosuppressed because of either heavy pretreatments or because of the earlier timing in the course of the disease. Unfortunately this Phase II trial had to stop early, because although the fever and the belly infections were still mild, the events were increased. But because these patients were not so immunosuppressed, antibodies developed which neutralized the treatment vector and 100 percent of the patients had progressive disease. The investigators did not find any BRCA 1 gene expression.

So I think of this story like the story of Penicillin's discovery. You identify and discover something but you don't know how to use it at the beginning so you have to go through serial trials and further development. Because the first generation viral carrier is the problem causing antibody production in the patients, a new vector was developed at Vanderbilt by Dr. Jeff Holt. The new vector was tested in a very small Phase I/II trial, but unfortunately the trial was stopped because there was no funding. This group does not belong to a company that has a lot of money. This is an investigator at an institution, and these studies are very, very expensive. So I put this out to you for those of you who are advocates. Get down on Capital Hill. More funding, more funding will make these developments progress.

Now P53. The P53 story has some similarities. The P53 trials were all intraperitoneal treatments using another virus, a genetically engineered common cold virus attached to the P53 gene. These early trials were performed in different ways at different sites such as Dr. Wolf's study at MD Anderson, and my own study at the "other cancer institute in Texas,"(I have to remind Dr. Gershenson of that sometimes). We gave the P53 treatments in different ways. We all did the important correlate studies to understand how this gene therapy works. Again, lots of blood and lots of belly fluid washes were used to figure out if and how the gene was being expressed. This slide shows one data point from one of our patients in the study. The results are very interesting, because one of the key things you want to see is that over multiple treatments over time, you actually see the amount of P53 go up. This means that the good copy you put in is actually working, and the tumor cells are going down in response. So that's exciting! But here again we have the same problems with antibodies. Because after the first one or two doses the antibody response is not a big deal, but as you keep giving these treatments with higher doses of the viral-gene vector, patients' antibodies go up. And as the antibodies go up, then the risk of having the vector neutralize before it does any good is significant.

There are a lot of people working on these Phase I and Phase II trials, the latter studies are designed to see if the treatments really work. Dr. Buller up at Iowa did one of the biggest studies, and interestingly this study also used gene therapy in combination with chemotherapy. I want to throw this concept out to you because many of these agents are in the early stages of development and may actually work better when combined with chemotherapy or combined with some of our traditional therapies. One hundred and fifty-five patients consented and participated. From this study, a lot of information was learned. Lots of different treatment strategies were tested in this group of women. As demonstrated in this slide, women received either one dose, a couple of doses followed by chemotherapy, or some received gene therapy in combination with chemotherapy. So what was the response? Survival was better in the patients who had multiple doses of gene therapy and then chemotherapy or multiple doses with chemotherapy than gene therapy by itself. So, again it looks very promising. We need to make better vectors so that the immune system doesn't fight against the drugs. We need to target the tumors better. There are a lot more combination studies that have to happen. But again, we just discovered Penicillin and we are trying to learn how to use it. It will happen!!

The next thing I want to talk about is Ovarex. I bring this up, not because I have any interest in the company, but because this is what my patients come in week after week and ask me about the monoclonal antibody, the Ca-125. "What about Ovarex? I read about it on the Internet." Again, these all represent developmental studies. This is the history of this antibody story. Several years ago a monoclonal antibody against CA-125 was developed for imaging purposes in hopes of identifying earlier disease. During these studies, it was noticed that perhaps patients who had the imaging agent did better in recurrence and survival. Since that observation, multiple studies have been performed to look at this monoclonal CA-125 antibody as a therapy. One strategy was used as a consolidation agent, and you've heard that term before. Consolidation means basically you get your surgery, you get your first line therapy, which is usually carboplatinum and Taxol ,which often produces a clinical remission. and the consolidation therapy is there to try to keep it from coming back. So monoclonal antibodies make sense.

You know, you live your days by the Ca-125 when you have ovarian cancer. You know that most of your cancers make Ca-125, why not make an antibody against it because you know your cancer is making it and this may be a good way for your body to fight it. Some of the early consolidation trials gave more information on how to use antibody therapy. They then tested it in recurrent disease. Again, you can just see the developmental strategies going on. What's been learned so far is that when you give this agent, the Ca-125 antibody, in many patients, you get an immune response, and you get a specific immune response against the mouse monoclonal antibody which is part of the monoclonal antibody. Women who have this antibody response will probably actually do better. Ovarex is not yet FDA approved. So it is not available for use outside of a study. I have had many patients come in and say, "why can't I have it?"

Unfortunately, the treatment is not available, even for compassionate use. The hopeful news: the big trial is going to hopefully get FDA approval. It is underway and it is open at several institutions. It is open at our institution within a few months and about 17 other institutions nationwide. This new trial is a very, very specific trial, so eligibility is very strict. This trial uses Ovarex in the consolidation phase, so you had to have had your surgery, you had to have had very minimal disease at the completion of your surgery. You had to respond to your platinum and Taxol, and then have a Ca-125 less than 65 by the third dose of your chemotherapy. So very, very specific. But certainly if you're interested in it and where it's open then 1-800-4-CANCER can help.

Monoclonal antibodies, not only for Ca-125, are being developed for ovarian cancer treatment. Other targets include the epidermal growth factor receptor (EGFR) that you've probably heard about. The GOG has an open Phase II trial right now at several institutions. It was open back in April of 2002. Very slow entry. And, again I think this is because a lot of people don't know about it. Or, they are not close enough to the institutions. But, recognize that it had been opened but right now it is suspended for an interim analysis, and hopefully will be opened again within the next six months or so.

You heard about Her-2-neu and Herceptin. It works in breast cancer, why can't it work in ovarian cancer? Well, a Phase II GOG trial was done and unfortunately, as you heard, only 12 percent of tumors over expressed the protein which is a requirement for treatment. The response rate was less than 10 percent. So this is probably not the monoclonal target for ovarian cancer. In fact it's definitely not. We need to look further.

Lastly, and just for a second, I want to mention designer drugs. What about Gleevec? It's the magic bullet for CML. And the reason for that is because this is an example of one disease that has one major genetic problem. It has a rearrangement in a chromosome that produces a molecule that blocks a very, very important molecular mechanism in the cell. What Gleevec does is it blocks that process from happening. Unfortunately, we don't have just one very specific genetic problem in ovarian cancer, so Gleevec or a Gleevec type drug for ovarian cancer is a little bit tough to say that this approach is going to make much of an improvement. So we look again. Here's that epidermal growth factor. We talk about blocking it with a monoclonal antibody. Well we can try to block its active part down here (as is shown in the slide) with a designer drug, and that's a drug you may have heard of called Iressa. Once again we have some GOG studies opened, or in a suspended phase to be re-opened once an analysis is done. GOG17E looks at Gleevec and 170C at Iressa. These should be posted on the web sites for you. Once again 1-800-4-CANCER can help.

"So why the delay?" This question is what I hear from my patients all the time. "Why the delay? Why can't I get the drug? Why can't these trials happen in a center closer to me?" I think now after hearing this information all morning, you appreciate the complexity of all of this work. The team approach and the fact that these studies have to be done in a very specific way. Not every place can do it and there is not enough money to bring the trials to everybody for that reason. So funding is the main issue and once again if you are advocates get out there and get on Capitol Hill to help us get more funding to get this done. It's also getting much harder in our institutions because of all the red tape and paperwork to do human subjects research. I think the government, and I know Dr. Birrer works for the government, but it may be getting a little too tight on some of the regulations that we have to deal with day to day. Some of this work is very difficult to produce. These are biologic treatments. They are not drugs and so they are in limited quantity. With that I thank you for your attention and we will take questions at the break.

David Mutch: Next we will have Dr. Larry Copeland and Dr. David Gershenson. Dr. Gershenson is the head at MD Anderson, and Dr. Copeland is the Chairman of Ohio State University--the national football champions. I will say that before Larry says it. Karen why don't you make an announcement. You will be able to get this whole session downloaded from a computer site, and Karen will tell you how to do that.

Karen Carlson: Just as you all know, we are actually taping this session and it is going to be transcribed and then it will be downloadable from our GCF web site, which we will provide for you at the end of this course. While you are here it's www.WCN.org, and then you have to go to the Gynecologic cancer button that is on the site. It's going to be downloaded from our site, or you can just call our office and we will send you a hardcopy in the mail. You need to give us about three to four weeks to make that happen after this meeting. You can call our number at (312) 321-6810.