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Drug targets on a cell
The past two decades of biomedical research have yielded an enormous amount of information about the molecular events that take place during the development of cancer. With this added knowledge, scientists are creating new drugs such as Herceptin and Gleevec, that target the molecular alterations involved in the biological pathways important in cancer. The hope is that by targeting specific alterations in cancer cells, these innovative therapies will be more effective in killing tumor cells and less harmful to normal cells. As a result, they should also have a major impact on survival and quality of life of the cancer patient.
Edward A. Sausville, M.D., Ph.D., and Louise B. Grochow, M.D., are National Cancer Institute (NCI) scientists who play major roles in helping to develop new cancer drugs. Dr. Sausville, the associate director of the Developmental Therapeutics Program of the Division of Cancer Treatment and Diagnosis at NCI, is primarily involved with pre-clinical evaluation of drugs, while Dr. Grochow’s responsibilities as chief of the Investigational Drug Branch at NCI are to develop, monitor and implement clinical trials. BenchMarks interviewed them prior to their presentations at the Science Writers’ Seminar on March 11, 2002, in Bethesda, Md., titled “Molecular Targets in Cancer Therapy.”
One of the purported advantages of molecularly targeted drugs is that they are expected to be less toxic to normal cells than standard chemotherapies. In the trials with targeted therapies so far, is this turning out to be true?
Dr. Sausville: Early returns with Gleevec and Iressa are encouraging because there have been positive clinical responses without the common toxicities seen with usual anti-cancer agents. However, it would be wrong to think that these agents are without any toxicity. Clinical experience will likely define “agent specific” toxicities, such as the skin rash commonly seen with molecules like Iressa. While most patients seem to experience improvement in the toxicity either spontaneously or with alterations of dose, some do not. The long-term consequences of these newer molecules will need to be considered carefully as the information emerges.
Dr. Grochow: Although, overall, the new agents are less toxic than traditional chemotherapy, trastuzumab (Herceptin) is now known to cause damage to the heart muscle in a few patients. Some EGFR (epidermal growth factor receptor) agents can produce diarrhea and a severe acne-like rash, and bleeding into the lung has been seen in some patients with lung cancer treated with anti-VEGF (vascular endothelial growth factor). None of these agents is as simple to take as acetominophen (Tylenol), and all are much harder than strategies for not getting cancer in the first place: eating five fruits and vegetables a day and not smoking.
Does a molecular-targeted approach to cancer therapy have any implications for restructuring clinical trials?
Dr. Sausville: Yes and no—if the drug can be aligned to a particular target that is responsible for actually sustaining the disease, such as Gleevec, then conventional trial designs will probably suffice, as was the case with Gleevec. But if the drug is affecting one of a number of aberrant pathways in a tumor cell, then potentially we will need to assess the actual target pathway to help decide the correct dose and schedule of the agent before devising new trials to combine the drug with agents directed at the other aberrant pathways.
Dr. Grochow: Many of the novel targeted agents differ from older agents in two critical ways that alter the conduct of both early and later clinical trials. In traditional dose-finding trials in cancer, doses were increased until unacceptable toxicities occurred; the more drug you could give, the more cancer cells would die. Some newer agents may have dose-response curves that do not steadily increase (like interferon, where particular desirable effects may diminish at higher doses). Some may not produce any additional benefit at higher doses. Some are not toxic at any plausible dose. So we can’t use conventional phase I dose escalation plans to select the dose and schedule for subsequent studies. We have to invent new ways to determine whether the drug is affecting its target in the desired way, and whether giving higher doses produces additional useful effects.
In standard phase II trials to estimate activity, older cancer drugs produced tumor regressions. These regressions were the basis for deciding to proceed with large efficacy studies to support widespread clinical use and drug approval. Many of the novel agents don’t produce regressions in tumor models; they slow the growth of the cancer. That’s easy to see in uniform mouse models but impossible to determine in individual patients with very variable clinical situations and rates of disease progression. So in phase II trials, new designs that compare the time for tumor progression, or measures of clinical benefit (reduction in pain, increased ability to perform regular activities), or that evaluate novel endpoints (metabolic activity of the tumor using imaging studies, for example) may have to be incorporated in early trials. For relatively quickly growing cancers, actual patient survival may be the endpoint in a phase II trial of some novel agents, but that won’t work for more slowly progressive disease states.
And then there are new agents like imatinib mesylate (Gleevec) — when it turns off the growth signal from Bcr-Abl, no new cells divide and older chronic myelogenous leukemic (CML) cells die off in days, so blood counts promptly returned to normal and the patient’s well-being was evident within the first month of treatment. Some patients in early trials with the small molecule EGFR inhibitors like Iressa and OSI-774 have had tumors shrink, even though the pre-clinical models suggested that there would only be slowing of tumor growth.
Dr. Sausville, you pointed out that the reason for Gleevec’s success is that it targets a unique protein in leukemia cells that the body doesn’t normally produce. This is in contrast to many cancer drugs that target proteins that are either under- or overexpressed in cancer cells, but are found in normal cells, and so, in effect, are not foreign to the body. Is there any intentional attempt to identify other unique proteins in tumors, such as Bcr-Abl protein in CML patients?
Dr. Sausville: Yes. NCI’s Cancer Genome Anatomy Program (CGAP), and its allied efforts to isolate full length cDNAs from tumors, are among the initiatives that will tell us about genes encoding protein molecules that may be present in tumors but not in normal cells. A more difficult question, though, is deciding about the functional importance of the expressed protein, and whether it actually contributes to the development of the tumor or is a “bystander” reflecting where the tumor originated. The latter types of targets, while not as unique as the Bcr-Abl example, still might be the basis for useful therapies, indeed as the work developing targeted toxins by many investigators including the NCI’s own Drs. Ira Pastan, David Fitzgerald, and Susanna Rybak has demonstrated.
In the new budget proposed for fiscal year 2003, “Molecular Targets of Prevention and Treatment” is one of NCI’s scientific priorities. What kinds of programs have been initiated in the last year or two to move forward with this approach to therapy?
Dr. Sausville: We started an extramural Molecular Targets Drug Discovery Program where investigators can use NCI resources — people, in-house expertise at our Frederick campus — to develop a particular molecule as a drug target. Forty research groups are currently supported by this program. (http://dtp.nci.nih.gov/branches/gcob/gcob_web9.html)
Another NCI program, the Rapid Access to Intervention Development (RAID) program which began in 1998, is designed to speed up the pre-clinical testing for promising drugs. This program targets academic laboratories that have novel candidate compounds, but lack specific resources or expertise to develop them further. (http://dtp.nci.nih.gov/docs/raid/raid%5Findex.html)
Dr. Grochow: To enhance the ability to incorporate translational research into early clinical trials, the IRT-MTA (Interdisciplinary Research Teams for Molecular Target Assessment) cooperative agreements have been funded to support extramural teams with expertise in a molecular target area. The funds will allow researchers to develop clinically- usable probes (imaging tests, assays, etc.) to determine whether new targeted agents actually are having the desired effect on the planned target in pre-clinical models and in patients.
The early clinical trials program (early clinical trials contracts and cooperative agreements) has been reorganized in several ways:
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to increase annual accrual to evaluate more targeted agents;
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to decrease the time from solicitation for trials to completion;
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to simplify reporting procedures and integrate clinical trials databases for enhancing safety reporting and patient safety;
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to support the integration of translational endpoints in early clinical trials to inform decisions regarding further development.
What are some unique resources that NCI has to offer to scientists who are interested in molecular targets?
Dr. Sausville: Expertise in discovery (screening and evaluation in animal models) and development (studies in animals and development of dose forms and assays for use in humans); discovery resources include collections of compounds and extracts from natural sources; and databases—open and free to the public—of how candidate drugs perform in screening assays. These databases may be linked to the presence or action of particular molecular targets. (http://dtp.nci.nih.gov)
Is it true that the rate-limiting step in drug development is often the translation from laboratory to the intact animal — that is, once the drug has been shown to affect a particular target by some assay, the difficult part is to achieve high enough levels in the blood and tumor for the drug to be effective?
Dr. Grochow: Sometimes the rate-limiting step is drug synthesis, sometimes it’s just the time it takes to do the toxicology. More often it’s finding an optimal “drug.” Frequently, the first proof of principle compound in the laboratory isn’t really suited to be a medication — it’s not soluble, can’t be given by mouth, has too short a duration of action, or is too toxic to use in an animal, let alone a patient.
Are there programs or funds available at NCI to help academic scientists try to solve some of these problems?
Dr. Sausville: Yes. The RAID program for particular candidate molecules and the new R*A*N*D (Rapid Access to NCI Discovery) program for molecules at an earlier stage in their development are programs to address these sorts of problems. These are described on our website: http://dtp.nci.nih.gov.
Since many common tumors actually contain dozens of potential targets, might it be possible to design a single agent that targets more than one defective protein? Are there any efforts to create such a molecule?
Dr. Sausville: Yes. Indeed, some of the most promising agents of this type can target many different proteins. This is exemplified by SU6668 from the Sugen Company, which targets at least three different growth factor receptors; Millenium’s PS341, which by affecting the proteasome can alter the behavior of a number of important cell cycle regulatory proteins; or NCI’s 17-allylamino 17 demethoxygeldanamycin, which can affect many molecules that talk to the drug target, heat shock protein 90 (hsp90).
Are there any classes of molecules that appear to be particularly effective as targeted drugs?
Dr. Sausville: I think recent history would point to certain protein kinase antagonists, including Gleevec and Iressa, as well as the proteasome inhibitor, PS341.
Dr. Grochow: Not at this time. Antibodies to ErbB-2 or Her2/neu (trastuzumab or Herceptin) and to certain leukemia cell targets are the first targeted agents to reach the market, but they have been followed closely by small molecules like imatinib mesylate (Gleevec). Because drugs like imatinib mesylate are used in patients with a disease that has a critical target (making a treatment decision based on the presence of the molecular target), they may help a larger fraction of patients than when a treatment is used for all patients whose tumors look alike under the microscope (making a treatment decision based on the traditional histologic diagnosis).
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Text Transcript
Normal Cell
When the epidermal growth factor (EGF) binds to the EGF receptor on the surface of a cell, it initiates a growth signalling pathway. This pathway turns on a gene associated with cell division, which causes the cell to divide into two new cells.
Cancer Cell
Many cancer cells have too many EGF receptors on their surface. Binding of EGF to these receptors results in excessive signalling along growth pathways, leading to unregulated cell division and tumor growth.
Cancer Cell plus Drug
Many cancer drugs currently under development work by targeting the EGF receptor. Some of these drugs target the signalling portion of the receptor inside the cell. Drug binding prevents the receptor from activating the growth pathway. Administering only enough drug to disable some EGF receptors on a cancer cell while leaving a few active will hopefully restore normal signalling and cell division, thus inhibiting tumor growth.
Audio Clips
- Louise B. Grochow, M.D., chief of the Investigational Drug Branch, National Cancer Institute speaks at the March 11, 2002, Science Writers Seminar on Molecular Targets in Cancer Therapy:
Theory to Therapy: Redesigning clinical trials based on advancements in molecular targeting (Part 1)( Audio – Length: 03:49 )
Text Transcript
Louise B. Grochow, M.D., chief of the Investigational Drug Branch, National Cancer Institute speaks at the March 11, 2002, Science Writers Seminar on Molecular Targets in Cancer Therapy:
Theory to Therapy: Redesigning clinical trials based on advancements in molecular targeting (Part 1)Dr. Grochow: So anyway, as you heard, Dr. Sausville’s motto is ‘Molecules to Man,’ and CTEP’s motto is, ‘Theory to Therapy.’ That is to say we get an agent that’s finished its clinical testing, its clinical toxicology, and we’re the ones who have to turn it into a real treatment.
So one question is, in terms of the molecular models issues, how is molecular development in cancer changing to address these issues that have been raised by agents that are directed at new targets. You’ve been touching on that a little bit throughout the morning. The first area that you heard about was actually the agent selection. Initally, agent selection was with mouse xenograph models and so on, but they more or less didn’t mimic any real human tumors.
Under the new model, we’ll be looking at what are commonly called now credentialed targets and molecular models that exhibit those targets — tumors that are diagnosed in a new way based on what we know about what’s going on and how that makes a cancer cell a cancer cell.
A credentialed target is — I’ll go over that a little bit more later — but a target that really is essential in the cancer cell’s being a cancer is a well-credentialed target. The best example of that — I’ll have a little bit later — is in chronic myelogic leukemia
In terms of priority, the best drugs are the ones that killed the biggest fraction of cells in the preview test. That was a great agent.
Now, we ought to be inhibiting the growth of cells, because if you can take a patient who’s got metastatic disease but only has three 1-centimeter, asymptomatic tumors in their lung, and you can make that tumor stop growing — even if the patient has to take something every day for the rest of their lives, if you can make it stop growing at that point when they’re asymptomatic you’ve suddenly turned a lethal disease into something that’s more like diabetes or hypertension.
It’s changed the way we’re going to have to do trial design. Previous trial designs were imperical – we just kept giving bigger doses until you couldn’t give bigger doses without threatening people’s lives. Whereas now they’re going to be hypothesis driven, driven on — as you heard about from some of the models Ed was talking about – on being able to show that the agent really has affected its target in a human being the way it affected the target usefully in a mouse.
And in terms of what dose point you’re going to use, it used to be just use the endpoint of toxicity, and now we’re going to be looking at molecular effect. There are all kinds of extra complications to doing clinical trials when you’re looking at molecular effect: When do you measure that; How often do you measure it; What do you measure? And in terms of deciding what the endpoint is, there are traditional trials where we were trying to look at patients, we did very ordinary doctor kinds of things — we did histories and physical exams repeatedly while the patient was receiving the investigational drug. We did standard clinical laboratory testing and standard X-ray kinds of imaging. All of that’s still going to have to be done in the new model, but in addition, we’re going to have to be looking at very complex issues — whether that’s investigational imaging agents, whether that’s biopsies looking for specific endpoints or collecting peripheral blood and extracting tumor cells out of the blood to see if they’ve been affected.
- Louise B. Grochow, M.D., chief of the Investigational Drug Branch, National Cancer Institute speaks at the March 11, 2002, Science Writers Seminar on Molecular Targets in Cancer Therapy:
Theory to Therapy: Redesigning clinical trials based on advancements in molecular targeting (Part 2)( Audio – Length: 02:49 )
Text Transcript
Louise B. Grochow, M.D., chief of the Investigational Drug Branch, National Cancer Institute speaks at the March 11, 2002, Science Writers Seminar on Molecular Targets in Cancer Therapy:
Theory to Therapy: Redesigning clinical trials based on advancements in molecular targeting (Part 2)Dr. Grochow: In terms of how we decided previously to go on a trial, traditionally in phase I in those dose finding trials, it was any patient with any solid tumors and some patients with solid tumors and hemologic malignancies would go into phase I.
Now the question is going to be is the eligibillity going to based on the patient having the target — is there any point in using a drug like Gleevec in a patient who doesn’t have that target, even in a phase I setting. Let me limit somewhat the patients who undergo phase I. It may make phase I trials take longer to do.
In phase II, those activity trials we talked about earlier, they’re going to change too because the traditional phase II role was to see what Dr. Sausville showed you; tumor shrinkage. But many of the new agents may not cause tumor shrinkage and they’re looking for tumor stabilization, the elimination of progression of the disease.
That’s a fairly easy thing to show if you’re looking at a bunch of completely identical mice with completely identical tumors of completely identical sizes and you can look at ten and twenty mice in a group, but in human beings, when you’re dealing with tumors of very varied progression rates which are unpredictable and change over time, showing that you’ve stabilized a tumor in the short term is not a very easy thing to do.
When are you going to look at the endpoint? Typically, for a phase II trial previously you gave the treatment for four weeks or eight weeks and then you did another X-ray, CAT scan or MRI. If the tumor had shrunk, you said, ‘Oh, that seems to be helping you, we’ll continue.’ And that was a positive affect in terms of moving an agent along.
But with the new model, we’re looking at tumor stabilization. Maybe we’ll be looking at establishing functional — and we don’t know when those should even be looked at. There’s some evidence, in terms of Gleevec, that within days of starting treatment you can see changes in the metabolic profile of extensive tumors. You may be able to look a lot sooner, but there are other agents where it may take a long period of time before you’d want to do that testing. We don’t know when those research X-rays even should be done yet.
- Louise B. Grochow, M.D., chief of the Investigational Drug Branch, National Cancer Institute speaks at the March 11, 2002, Science Writers Seminar on Molecular Targets in Cancer Therapy:
Issues regarding expertise, cost, and dose-finding in molecular targeting trials (Part 1)( Audio – Length: 01:34 )
Text Transcript
Louise B. Grochow, M.D., chief of the Investigational Drug Branch, National Cancer Institute speaks at the March 11, 2002, Science Writers Seminar on Molecular Targets in Cancer Therapy:
Issues regarding expertise, cost, and dose-finding in molecular targeting trials (Part 1)What we need to put together in terms of extras to do that kind of a clinical trial, used to be that the trial design was done on handout from Dr. Sausville’s group who got it through clinical screening, toxicology and medical oncologists. But to do these new kinds of trials with new endpoints, we’re going to need translational experts who can participate in the trial design. We’re going to need people who know what that the research x-rays are, or who understand what the biopsies results are, and who can interpret that during the course of the trial and say, “Hm, maybe we’re doing that biopsy too soon. Maybe the next batch of patients we need to biopsy at the end of the third week.”
In terms of the kinds of experts in addition to the good old medical oncologists, and an analytic chemist, who can do pharmacokinetics — basically just measuring drug in the blood to see if the amount in human being’s blood is similar to what it took in a mouse to get some kind of useful effect — we’re going to need those same people, but now with specialized research pathologists, specialized imagers, specialized radiologists who are used to doing especially safe biopsies. And in terms of endpoint, like I said before, it was based on toxicity and how much drug was in the blood using a plasma assay. But now you’re going to be doing that, plus whatever the molecular target is. Plus it’s probably going to double, for doing single-patient in Phase I trials, and that’s roughly the cost at the site.
Different companies double to deal with their internal manpower in dealing with the trial.
- Louise B. Grochow, M.D., chief of the Investigational Drug Branch, National Cancer Institute speaks at the March 11, 2002, Science Writers Seminar on Molecular Targets in Cancer Therapy:
Issues regarding expertise, cost, and dose-finding in molecular targeting trials Part 2( Audio – Length: 01:41 )
Text Transcript
Louise B. Grochow, M.D., chief of the Investigational Drug Branch, National Cancer Institute speaks at the March 11, 2002, Science Writers Seminar on Molecular Targets in Cancer Therapy:
Issues regarding expertise, cost, and dose-finding in molecular targeting trials Part 2In terms of finding studies, I did go through a little bit this week — I didn’t know we’d discussed phase I eariler — but we used to talk about a maximum tolerated dose, that issue of when the white count’s too low to go any further. But now we’re talking about potentially doing something called a target effect dose, when enough of the drug is being given. And there’s some real important reasons to do that, to establish that relationship, because there are agents that may have no toxicity at any dose that can be given. {Endostatin} is an example of an agent that we really couldn’t find a dose in a mouse that you could give that would make the mouse sick. It’s a very safe drug.
For some expensive agents, like G3139, that are very expensive to make — antibodies or antisense molecules, they may have useful effects at doses that aren’t toxic and that would be a lot cheaper to give than if you gave ten times more of the dose. The typical relationship that a pharmacologist looks between how much drug there is and how much response is usually some version of this S-shaped curve. And monotonic means it steadily increases until you finally get to a maximum effect. Some drugs don’t have any maximum effect — the more you give, the more cells you kill but you start killing cells you don’t want to kill, like white cells and immune cells and things like that.
But for interfueron, in fact, you get to the peak of the useful effect and if you keep increasing the dose, the effect actually drops off and you get some other effects that you don’t want but you don’t get more of the effect that you do want, you’re actually getting less of it. So establishing what that right dose is difficult
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1. Growth Pathway of Normal Cell
2. Growth Pathways of Cancer Cell
3. Cancer Drug and Growth Pathway
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