Rosenthal, Eric T.
Vanderbilt-Ingram Cancer Center's place in the Guinness Book should be assured the evening of June 7, when the third of three of its faculty members assumes the mantle of oncology-organization leadership during the same calendar year.
At that time, Vanderbilt-Ingram Deputy Director and ASCO President-Elect David Johnson, MD, will drop the “elect” and start his presidential term at the American Society of Clinical Oncology, making the Nashville cancer center home to three sitting presidents of major cancer organizations.
Dr. Johnson's one-year term will overlap with Vanderbilt-Ingram Director Harold Moses, MD's two-year term as President of the Association of American Cancer Institutes (AACI), and Cancer Biology Chair Lynn Matrisian, PhD's one-year term as President of the American Association for Cancer Research.
But whether this unique situation is considered a convergence or coincidence is secondary to what the three want to make of it: a special opportunity for the three societies to collaborate in the fight against cancer, according to Dr. Moses, who also served as AACR president for 1991–1992.
Working Together on Clinical Trials
In separate telephone interviews, all three reiterated that they wanted to advance the field of cancer research as it relates to patient care by working together on clinical trials.
Dr. Johnson—who is also Cornelius Abernathy Craig Professor in Medicine and Surgical Oncology and Director of the Division of Hematology/Oncology—noted his and his colleagues' mutual desire to develop the fields of cancer biology and cancer care.
“We know our knowledge is advancing at unbelievable speed,” he said, “and since some of the paradigms for clinical testing are outdated for some of the targeted therapies now available, it's important to develop some solutions so we can move forward.”
Moving forward in this case means developing a “white paper,” as yet untitled, on changing the paradigms for clinical trials by including basic scientists in trial design.
Hal Moses: Transforming Growth Factor Beta
Dr. Moses, a basic researcher who trained as a pathologist, is known for his work with transforming growth factor beta, which his lab discovered as both a tumor promoter and tumor suppressor under different circumstances.
Dr. Johnson referred to him as “a bona-fide basic scientist in a physician's body,” a description Dr. Moses found amusing.
“We've been working very hard on this initiative,” Dr. Moses said. “After we found out that all three of us would be presidents, we got together and batted around ideas to see what we could do to come up with a common initiative or set of initiatives.
“It actually didn't take us very long to settle on clinical trials, and that is to establish—and it's difficult to state so it doesn't make someone angry—a different mechanism of trials where patients are extensively studied using a lot of biological correlates involving clinicians of all types, and basic scientists, who tend to get left out when you're planning clinical trials, as well as having industry at the table.
“We have to try to develop trials more intelligently. If you look at the INTACT [Iressa Non-small cell lung cancer Trial Assessing Combination Treatment] and IDEAL [Iressa Dose Evaluation in Advanced Lung cancer] trials, I think retrospectively we'd consider it's absolutely not the way to test the new targeted therapies.
“But if we can preselect the patients, figure out a way to predict for response—just like the BCR-ABL translocation predicts for chronic myelogenous leukemia and responsiveness to Gleevec—then we might be able to do a much better job and not lose promising drugs, which came close with Iressa because the trials were negative.”
Dr. Moses went on to explain that it was clear to those involved in the trials that as many as 5% to 15% of non-small cell lung cancer patients were receiving enormous benefit from Iressa, and added that if the patients had been preselected the response rate would be something like 70% to 90%, making it more like a Gleevec story.
“There's a lot to be done in terms of better diagnosis,” he said. “We need biomarkers and have to subdivide those, and then we need the means to detect those who are most likely to respond to a given therapy.”
Different Pharmaceutical Companies
Another issue he cited was difficulty in trying combinations of different agents when these agents are the products of different pharmaceutical companies.
“Changing the paradigm is necessary because of advances in many areas, including our ability to better diagnose using genomic or proteomic footprinting as well as the availability of many new targeted therapies that need to be tested,” Dr. Moses said.
“Part of our plan is based on advances here [at Vanderbilt-Ingram], particularly in the proteomics area, where I think there's real promise, as well as the DNA microassay approach elsewhere. You can't look at any one or combination of two or three markers and get the predictive power you need to make the right decisions—you need to look at a dozen different markers or perhaps more.”
Dr. Moses said 24 individuals representing AACI, AACR, and ASCO, as well as industry, government, and patient advocacy, already had a preliminary meeting at the March AACR Annual Meeting in Orlando. The group plans to follow up with more meetings and a retreat.
Lynn Matrisian: Topic at Top of List
AACR's Dr. Matrisian, who is also Ingram Professor of Cancer Research, said, “You might not think that as a basic scientist I'd be that interested in the clinical trials part as the initiative we'd take, but it was really right on top of my list of what we could do, and this stems from my own research experience and where I see the field going.”
Dr. Matrisian related how she first started out as a medical technician in a genetics counselor's lab and later, as a post-doc in Strasbourg, France, she cloned a gene that turned out to be the first full-length CDNA for a member of the matrix metalloproteinase (MMP) family—proteases that had been thought to be involved in cancer metastasis for many years.
“Although I'm a molecular biologist, I originally trained as a cancer biologist and took my work in a cancer biology direction when I came here in 1986. The pharmaceutical companies got very interested, and I remember giving a CDNA to a pharmaceutical company early on and they were doing crystal structures and making inhibitors.
“That developed into making small molecule inhibitors for matrix metalloproteinase inhibitors that went to about a dozen Phase III clinical trials that did not work. The [inhibitors] worked great in mice, but in clinic there were only a few hints that it might work, and some of the trials went the wrong way. The trials were stopped, and the field crashed.
“I could see this coming and started to look at what had gone wrong,” she said. “How could we as basic scientists be so wrong about MMPs?”
Dr. Matrisian went down the hall from her office to see medical oncologist Mace Rothenberg, MD. “He taught me about clinical trials, and I taught him about MMPs and we looked at what went wrong. For the last few years my lab has been working on what we should have done before had I known how the clinical trials would be run.
“There have been lessons learned from this experience,” she continued. “Had I known more about what was going to happen in the clinic, I would have done my studies differently. I did my animal studies the way the literature says to do them.
“I never really thought about if this work goes to clinical trials. And now, for any targeted therapy that comes down the road, I have a much better idea about what I need to know up front. I won't make those mistakes again. I'll develop an assay earlier and not wait until it gets into the clinic and someone says, how do I know this is the right dose?”
Dr. Matrisian added, “If we don't want this to be just a random event, we have to have teamwork on something that's clinically relevant. If we want to be focused and use our time and resources to our best advantage, let's do it with some understanding of the endpoint and what's coming down the road so we're prepared for that.
“That's my incentive for wanting to do smarter clinical trials. There were thousands of patients treated with MMP inhibitors, and at the end when it didn't work, I had no clue why it didn't work. We didn't do the controls and don't have information from those trials. It was such a waste of time and money and patient opportunities not to get more information from those trials, and that's why I'm quite passionate about doing this initiative together and having basic science input into these trials, because it goes both ways.
Figure. (left to rig...Image Tools
“The basic scientist needs to know what happens in the clinic, but if clinicians know more about what the basic science is, they can design better trials.”
She explained that since basic scientists are so specialized, there may only be a few clinical trials they can help with, making it necessary to develop a system that will allow basic scientists to know what clinical trials people are contemplating, so that they can make relevant contributions.
Have Been Meeting All Along
Working together on this translational initiative at Vanderbilt-Ingram should not be a problem, because for years the three now-presidents have been meeting regularly on Tuesdays as part of the institution's 10-person Executive Committee.
Their offices were also designed in close proximity: Dr. Johnson's is directly above that of Dr. Moses and down the hall from Dr. Matrisian; and even their parking spaces are near each other.
ASCO's Dr. Johnson, who is internationally known as a clinician and researcher in lung cancer and experimental therapeutics and who has been an AACR member since the early 1980s, also brings a lymphoma survivor's perspective to the table.
“We're not just interested in making pronouncements,” he said, “we're interested in making things happen, and through the collective clout of these three societies we hope we'll be able to help advance the care of patients, prevent cancer if it's at all possible, and overall enhance the well-being of our society.”
First Question Asked at Site Visit
Will their total time commitments to their respective societies pose a leadership vacuum at Vanderbilt-Ingram?
Both Dr. Moses and Dr. Johnson noted that that also happened to be the first question they were asked during the center's NCI grant-renewal site visit last year. Citing the depth of their medical and scientific staff as well as administrative delegation, they added that it was probably better that they were serving their societies at this time rather than before the grant renewal.
© 2004 Lippincott Williams & Wilkins, Inc.