Episode III Transcripts

Introduction

Mark A. Israel, MD
Director, Norris Cotton Cancer Center
Dartmouth-Hitchcock Medical Center

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ISRAEL

In the history of mankind we're at the most exciting juncture in the development of novel strategies for approaching the cancer problem. Whether they are prevention strategies or improved diagnostics or enhanced treatments, there's just no doubt that the remarkable fund of basic science information that's been accumulated in the last several decades and is continuing to emerge, forms a remarkably exciting fertile ground on which to think about improvements for the care of patients.

Targeting Molecular Defects to Stop Cancer

Most of the recent progress and promise of cancer research is based on new understandings of cancer on a molecular and cellular level. What does this mean for treatment?

Robert Weinberg, PhD
Daniel K. Ludwig Professor for Cancer Research
Massachusetts Institute of Technology

C. Norman Coleman, MD
Director, Radiation Oncology Sciences Program
National Cancer Institute

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ROBERT WEINBERG

The big hope for the future is that if we understand the molecular defects inside cancer cells, we can target them, and we can create drugs that specifically interfere with those defects, allowing us to kill cancer cells selectively while leaving normal cells untouched, thereby reducing undesirable side effects, and there have been several home runs that have been scored in recent years using this rational drug design. Gleevec is perhaps the best known of these.

COLEMAN

Molecular therapeutics are therapies designed for a relatively specific molecular process. A perfect example is the drug Gleevec, which targets a mutation in chronic myelogenous leukemia and the mutation is the central feature of that disease, so without that mutation you wouldn't have the disease. If you can knock out the function of that mutation, the disease goes into remission. So molecular therapeutics are therapies designed to hit a specific molecular target.

What's interesting is a lot of the drugs that we use and that work, we really don't quite understand at the molecular level how they work. So as we understand even drugs like platinum and Taxol and so forth, a lot of them are molecularly targeted drugs when we understand their pathways.

Gleevec Applied to Other Cancers

Having had remarkable success at treating chronic myelogenous leukemia with Gleevec, scientists are trying it with other forms of cancer.

Gary Gilliland, MD, PhD
Professor of Medicine
Harvard Medical School

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GUILLILAND

The gene that drive the chronic myelogenous leukemia is one of a set of genes that we all have in every cell, there are 96 of them, they are enzymes that are called kinases, and the drug that Brain and his colleagues developed works a little bit like a key in an ignition switch, that in a cancer cell, if you turn these kinases on, it's little bit like a key turning an engine, one that causes that cell to grow and to divide and expand without any control, and the drug that he developed works to turn that key back off again. Now that's one key to one gene that causes cancer, CML. But we now know that out of these 96 other enzymes, kinases, most cancers appear to have the same types of keys in the lock on position, so we can try to identify those and try to identify compounds that are likely to be effective not just for treating other kinds of leukemias but for treating solid tumors. There's a gastro-intestinal tumor that's incredibly difficult to treat that turns out to have the same lock and key arrangement that chronic myelogenous leukemia has. Gleevec works very effectively in that context. So we believe that these findings will be extrapolatable to a whole variety of solid tumors that rely on these kinds of signals for their growth and proliferation.

Human Genome Project

The Human Genome Project sets out to identify all the approximately 20,000-25,000 genes in human DNA. The knowledge gained from this colossal effort serves as a source of vital information in cancer research.

Gary Gilliland, MD, PhD
Professor of Medicine
Harvard Medical School

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Related Link: http://www.ornl.gov/sci/techresources/Human_Genome

GUILLILAND

It's very exciting for us to try to identify the causes of cancers. We're focusing mainly on the most difficult leukemias like acute myelogenous leukemias or AML's. These are life threatening diseases, they're treated with intensive chemotherapies but only about 20% of adults who develop this disease will survive for five years. And we're taking the observations in CML and extending them into AML by going through the human genome and sequencing the DNA from leukemic cells from these patients. This wouldn't be possible were it not for the human genome mapping project, we've benefited dramatically from that, and we've already identified several genes from that that we think contribute to the development of AML and we've identified compounds that we hope will be the next Gleevec that will be used to treat AMLs. Dr. Stone is testing several of these in clinical trials now, they're called FLT-3 inhibitors and we're very hopeful that they'll have some activity or improve the outcomes for patients that have AML. And we and others are interested in trying to extend these observations into breast cancer, prostate cancer, investigators are looking at colon cancer for exactly these same types of mutations that cause the cancer so that we can then design drugs that will turn those genes back off.

Clinical Trial Phases

How does a clinical trial progress from basic concept to an approved treatment? What is meant by Phase I, II, and III?

Margaret Mooney, MD
Senior Investigator, Clinical Investigation Branch
National Cancer Institute

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MOONEY

Usually a clinical trial is actually the one of the last steps in a very long process of evaluation of a new treatment and a new drug or a new therapy. It begins with painstaking research in the laboratory. Development of new drugs in the laboratory then usually proceeds to testing in animals. Once testing is shown to be safe and potentially effective, then it is moved into clinical trials which are trials on voluntary human subjects. At that point, particularly in drug development--I am using that as an example--, there is a phase of clinical trials that a drug goes though in terms of evaluation. The first is something called a phase I trial, and in that trial the main goal or objective is to really try and figure out whether the drug is safe and at what doses is it safe and how is it best delivered. The second phase in that development and process is something called a phase II trial. In those types of trials you also continue to develop and to monitor the safety of the drug, but you are also trying to figure out if it is effective agonist a particular type of cancer. If the results of the phase II trials are promising, in both the terms of safety of the drug as well as in terms of effectiveness in terms of a particular cancer, then it moves into what we think of a final stage, which is a phase III testing.

MOONEY

Phase III clinical trials are large trials usually involving hundreds if not thousands of patients in which we are trying to test weather a new cancer therapy or procedure is better or better tolerated than the standard of care for that particular disease. They are usually conducted in multiple institutions across the United States, and the reason that there are so many patients involved or volunteer for these trials is so that we can have a high degree of confidence once the trial is over, and when we evaluate the results, whether the new treatment should replace the previous treatment.
Participating in a Clinical Trail

Why do some people chose to participate in clinical trials, while others decline?

MOONEY

I think that there are a lot of reasons that people don't participate in clinical trials. One is that there are some myths about participating in trials. People sometimes think that they are going to be treated with a placebo, or essentially no treatment, and that is almost never done in cancer treatment clinical trials. Another myth that I think prevents people from participating in trials that they feel that they will be treated like guinea pigs. And usually what we find when we talk to people who have participated in trials is that they felt quite the opposite, that they felt empowered by participating in a clinical trial. That they felt what they learned in participating in the clinical trial and though the care that they had received, they felt that they understood more about the disease, and about the options of standard care as well as potential new treatment.

MOONEY

There is really a whole system of protections in place for to protect the rights and the safety of anyone who participates in a clinical trial.

MOONEY

I think that the heart of safety, as well as insuring that a person understands what they are getting to when they participate in a clinical trial, is the informed consent process and that happens at a very local level between the person who potentially participates in the trial and the particular research team composed of the physicians as well as nurses and any other health care professionals at that institution that will be conducting the trial.

MOONEY

In that process the patient learns not what only is the purpose of that trial is but also what the risks and the potential benefits of participation. And it is important to remember that that process is not only a one time process--it is an on-going process as people continue with participation and clinical treatment trial. Particularly in cancer, but in any disease they are informed at all points as to what is happening, of the results of tests that are being taken during that to monitor the progress of that treatment. And at the same time as any safety issues come up, they also are made aware of those issues by the research team.

MOONEY

Patients and potential participants should also realize that their participation is completely voluntary, not just at the beginning, but anywhere in the process. They can decide at anytime to stop participating in a trial if they feel uncomfortable or if they no longer--for what ever reason--want to continue to participate. Their medical care will not be effected at all by there choice.

Learning about Clinical Trials

Margaret Mooney, MD
Senior Investigator, Clinical Investigation Branch
National Cancer Institute

Related Link: http://www.nci.nih.gov/clinicaltrials

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MOONEY

The National Cancer Institute has a large web site that gives a vast array of information on cancer in general, treatments, and also it's tied to a data base that would allow patients over the internet to review the trials that may be applicable to the type of disease that they have. And in addition to that, the American Cancer Society and patient advocacy groups all have web sites and are all happy to talk to patients as well as just provide all information on participation of clinical trials.

MOONEY

The first thing that I think that anyone should do is to talk to there physician. Let the physician know that they have an interest in participating in clinical trials. Then they can find whether there is an applicable trial in your area or nearby, and many clinical trials are run in the community and in community hospitals, and see if any of those are available and appropriate for that particular patient.

Clinical trials in children

The difficulty a family has in making the decision to place their child on a trial.

Eric Larsen, MD
Pediatric Oncologist, Norris Cotton Cancer Center

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LARSEN

It's very scary for a family that has just been told that their child has leukemia or some other form of cancer to also hear that we would like to do some research, and perhaps the treatment that we're going to give your child is research. Many families translate this into a guinea pig phenomenon and that we would like to do an experiment on their child. We spend hours with families to fully inform them of the true nature of these trials--to inform them that their children will not be guinea pigs and that the treatment they will be receiving has been tested and is thought to be not only safe but also effective. We also assure them that there are ongoing mechanisms to measure the success of the trial and that we follow the safety of the trial and that it's always an option for a child who started treatment on a clinical trial to come off that clinical trial.

Anti-Angiogenesis

A promising new treatment for cancer starves tumors of their blood supply.

Robert Weinberg, PhD
Daniel K. Ludwig Professor for Cancer Research
Massachusetts Institute of Technology

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WEINBERG

If we consider all of the various kinds of cells that are recruited into a tumor mass, perhaps the most important kind of cells that are recruited by the cancer cells are so-called endothelial cells, and these endothelial cells are specialized to make blood vessels, to make capillaries, why are the cancers to interested to recruit endothelial cells into the tumor mass? Simply because a cancer, a tumor tissue, requires a blood supply just like normal tissue. And therefore, without such a blood supply a tumor cannot grow to a diameter of more than lets say 1 or 2/10ths of a millimeter. Therefore the tumor needs a direct blood supply and how it does that is it seduces blood vessels to grow into the tumor mass, thereby supplying the cells in the tumor mass with nutrition and oxygen and thereby enabling the tumor mass to rid itself of carbon dioxide and all kinds of metabolic wastes that it needs to get rid of so that it doesn't poison itself.

WEINBERG

A highly attractive strategy for treating many kinds of cancers is to interrupt the recruitment of many endothelial cells by cancer cells. This recruitment leads to a process of blood cell formation which we call angiogenesis. And if one can block angiogenesis, one can prevent these endothelial cells from being recruited into the tumor mass and thereby block the cancer cells from getting access to the circulation and the much needed nutrients and oxygen that are carried by blood.

Until now attempts at interrupting angiogenesis have succeeded in a small number of tumors, but the anti-angiogenesis therapies have not yet been put into clinical practice because the success to date have been few and far between. However, if I were a betting man, and I am, I would bet there will be some striking successes in improving anti-angiogenesis therapy to the stage that it will be useful in treating many kinds of human tumors.