Beaming Out Tumors

There's no doubt we can deliver higher doses of radiation and still produce fewer side effects, says the chairman of the newest department on campus.

By Mary Ellen Miller

The field of radiation oncology has always been a different animal. Its practitioners don't treat patients with drugs or surgery, like other physicians who deal with cancer patients. Nor are they radiologists, who take images expressly for the purpose of diagnosis. Instead, they are a combination of both -- specialists who treat cancer with powerful energy of radiation.

At most medical centers, this distinctive specialty has long held departmental status. But at Johns Hopkins, where oncology evolved differently, the new Department of Radiation Oncology and Molecular Radiation Sciences didn't make its debut until July 1. This spring, after a national search, Dean Miller announced that the department's first chairman would be the homegrown Ted DeWeese. The affable DeWeese, 42, arrived at Johns Hopkins in 1991 for his residency, worked his way up from instructor to associate professor in oncology and urology in seven years and became director of the radiation biology research program in 2000. Known for his work in urologic malignancies, DeWeese and colleagues devised the first adenoviral gene therapy trial for prostate cancer, using a common cold virus as a "smart bomb" targeting only cancer cells while leaving normal cells alone. Widely admired by his staff, DeWeese is considered not only a top researcher but a superb clinician, mentor and "program builder and visionary."

What's the current state of radiation oncology?

There have been staggering advances in molecular-based technologies during the last five years that have affected the field in ways we only dreamed of before. Using molecular-based imaging, we'll be able to see tumors like never before -- not only what's in the organ we're interested in, but also the cells related to the tumor outside the organ. Also, we'll be able to see the function of the tumor and direct therapies specifically toward it. When radiation is given one way, for example, tumors respond far differently than if it's given another way.

What do you mean by that? What are the different ways tumors respond?

If a tumor depends, say, on a specific protein to repair its DNA -- and certain tumors use this repair pathway to greater advantage than others do -- then we might be able to deliver the radiation in such a way to those tumors that avoids activating this DNA repair system. We are now studying some of these alternative ways and have seen some very interesting results.

Likewise, there are certain drugs that target these DNA repair pathways that can be designed to seek out only the cancer cell and when combined with radiation destroy cells at a greater rate. We've designed several ways to get the drugs into those pathways, one of the most interesting being through common cold viruses called adenoviruses. By injecting the virus into the tumor we're irradiating, we've shown both in the culture dish and in animals growing tumors that this combination will kill seven times more cells with the same dose of radiation than with radiation alone. We're about to start a clinical trial based on this work.

In other words, you're killing more bad cells and fewer normal cells.

The upside of radiation is it kills cells very well. The down side is, normal cells can also be damaged and side effects can result. I view this as two problems. There's a physics problem -- Can we design ways to deliver the radiation more accurately? The answer is definitely yes. But there's some molecular technology involved, too. Can we understand how the normal cells respond to radiation, and tailor the radiation to minimize the damage? Again, I think the answer is yes. There are molecular techniques now available in nuclear medicine that allow us to watch the normal tissue function over time. We need to study these agents while we irradiate patients to learn how and when normal cells stop working and whether we can change this by how and where we deliver the radiation. That's never really been done before. So, I think these sorts of research efforts will be the next wave of techniques we'd like to see in place in the clinic.

From the physics point of view, we're now using a very sophisticated, computer-driven technique called IMRT (intensity modulated radiation therapy) that precisely shapes the radiation beam to the exact shape of the organ. We can actually modify the intensity of the radiation beam while it's on, putting little individually moving fingers of metal alloy in and out of the beam while it's pointed at the patient so the beam is shaped very precisely to that target. We also can use the gamma knife and our other radiosurgery techniques to treat tumors to within an accuracy of less than one millimeter. It takes resources -- both real capital and human capital -- to pull it all off, but there's no doubt we can deliver radiation at higher doses with fewer side effects.

And the risks?

There's a double-edged sword to all that precision. If you're right on target, precision is good, and if you're off a little bit, you might miss part of the tumor. We go to great lengths to use three-dimensional imaging to specifically localize the tumor. While important, that's one snapshot in time, and an organ like the prostate can move within the body. So we've also adopted some new 3-D ultrasound techniques to see the tumor every day before the patient is treated, and determine if the tumor has moved slightly on that particular day.

An even more precise way to see a cancer is to use a CT scan every day, so why not do that right before the patient's treated? I'd like to see us move toward using a CT scanner and a radiation machine in the same unit, so all could decide if adjustments are required that very day and then use the same machine to treat the patient right then. That allows us to be as precise as we could ever be.

Does that technology exist yet?

It has literally just been developed, and I've just heard that the first human have now been treated this way.

How expensive is that for patients?

Interestingly, from the patient's perspective, it won't be more expensive than what we presently do. It's certainly more technically challenging, so the costs to Hopkins are slightly higher, because it's not yet known how to best integrate this into a standard clinical setting. But that's our job, to be at the cutting edge. That's why we have research physicists, Ph.D.- and master's-level physicists who work with our physicians and biologists -- to understand the technology and apply it in the most reasonable fashion.

How many people are on your staff?

We have approximately 100 faculty and staff, and we're going to augment that a great deal because of our research potential. We're recruiting several members to our clinical-physician faculty. We're also going to begin the first division of medical physics research here, with a director and faculty. We'll start a new division of radiation biology, with substantial lab space in the new cancer research building and also recruit new scientists who do translational research. Altogether, we'll increase our faculty by approximately 12 members within three years, which is double our current number.

Give me an example of collaboration within the Oncology Center.

One interesting example is the work I do with tumor biologist John Isaacs, Saeed Kahn, a medicinal chemist, Samuel Denmeade, a biologist and medical oncologist, and myself, a tumor and radiation biologist and oncologist. Drs. Isaacs, Denmeade and Kahn wondered if one could take a drug that would normally kill a lot of cells and make it very specific to only cancer cells. It's called a pro-drug. When this pro-drug gets near a cell that makes a specific protein, like prostate-specific antigen (PSA) from the prostate cell, the PSA actually breaks up the drug and makes it active. We've been able to show, at least in the preclinical setting, that it won't kill normal cells, but when you put it on cancer cells that make PSA it will start to kill them. And when you give radiation, it kills about 10 times more cells. This means we could design drugs that enhance radiation's killing potential, but limit it only to the cancer cells.

Why was Hopkins so late in giving departmental status to Radiation Oncology?

In the 1970s, Al Owens [the first director of the Cancer Center] created a separate Department of Oncology with research at its base. The notion was that if you have excellence in research, then patients would receive the best possible care and residents would get the best training. His visionary concept was to put all the oncology specialties in the same house -- radiation oncology, medical oncology, bone marrow transplant, pediatric oncology -- everything except surgical oncology. More recently, as the biologic and physics aspects of radiation oncology grew, it became clear that we needed a new structure that allowed for greater growth and expansion.

So radiation oncology didn't evolve out of radiology.

Not at all. Interestingly, in 1895 X-rays were discovered by Roentgen. Very soon thereafter, even more fundamental from my field's point of view, was when Marie and Pierre Curie isolated radium and started treating patients. You could argue that the most important contribution in medicine has been radiation and physics and the discoveries by Roentgen and the Curies. All the radiology technology we have today stems from those understandings. I think it transformed medicine even more than drugs. It gave us the power to diagnose disease in non-invasive ways and then treat them with a powerful energy, radiation. I think that was a very fundamental time in the evolution of modern medicine.

How did you become interested in radiation oncology?

Where I grew up in Colorado, most people weren't on the college path. After high school, I worked as a mechanic at a Ford dealership and raced motorcycles. After three or four years, I started college, and realized I loved science. I got a degree in chemistry, but then I wanted to know more about human biology, the interaction of cells with chemistry, so I went to medical school. I was doing research during that time on a disease called malignant hyperthermia, which can be fatal when patients are given anesthesia. Suddenly the patient's muscles contract so tightly that they develop an elevated temperature and die. I worked with a scientist who was trying to develop a simple blood test that would predict who had the disease and who did not. It was the first time I was exposed to true translational science -- here's a clinical problem, here's the biology, now how do you mesh those two to benefit patients. Suddenly, I knew that's what I wanted to do.

How did you get to Hopkins?

After medical school at the University of Colorado, I did my residency here 13 years ago. It's been a fantastic place for me. The patients I've treated and the colleagues with whom I've interacted have been inspiring -- the highest quality scientists and clinicians. I have never been turned away when I asked for help or opinions from any colleague. Hopkins is just a fantastic environment in which to grow professionally and personally.

What are your plans for the department?

The initial thing is setting the tone that it's a new time for radiation oncology. The expectations for excellence in research are really at a different level. I know our faculty will embrace the opportunities to grow their research careers and practices, translating what we do on [the research] side of the street in the clinic. Recruiting high-quality faculty and staff to help us augment this new department will be a tremendous task. There's a lot of planning that goes on before adopting new technologies, and I look forward to that as well.

Also I'd like to have more interactions with the Johns Hopkins Applied Physics Lab. The scientists there think in a whole different way. I think a fresh look at our problems by some highly skilled physicists and engineers could benefit everyone. APL has a lot of contact with the Department of Defense, and if you can hit a flying missile, hitting a tumor seems to me a little less complicated. I think it would be an interesting marriage of concepts and talents.

Beyond that, what do you think the future holds?

I keep a paper on top of my desk. It was published in 1998 and changed the way I began to think about radiation and how to deliver it. There are ways to use subatomic particles, which can be very precisely directed at tumors, to treat patients with great effect. The challenge is to do it without needing expensive facilities. This, however, will require the collaboration of many separate disciplines, from physicists and engineers to physicians and biologists. It is a large task. But if any place should be doing it, we should.

Will you?

Absolutely. It's not clear exactly where we sit right now with respect to this. But we need at least to begin to explore the opportunities. I want us to evolve in ways that can improve our patients' lives. Because ultimately that's the goal. The rest of it is kind of an interesting dance.

-- Reported by Mary Ellen Miller