As a young graduate student studying endocrinology, John Copland, Ph.D., realized quickly that scientific knowledge alone wouldn't fulfill him. Studying the hormones that influence animal reproduction can sometimes foster such revelations. "I thought to myself, I don't know if I can do this for the rest of my life," recalls Dr. Copland, now a molecular biologist at Mayo Clinic Cancer Center in Jacksonville, Fla. "I wanted to make an impact on human disease. That's the interesting component; that naïve vision I had as a graduate student is playing out."

The playing field for Dr. Copland's vision is renal cell carcinoma, the most common form of kidney cancer. Although considered relatively rare, it holds a fearsome distinction in the field of cancer research. While incidence and mortality rates for many cancers have declined over the years, that's not so for renal cell, which currently results in about 36,000 new cases each year and about 14,000 deaths, according to the American Cancer Society.

Adding weight to those figures are statistics showing that renal cell carcinoma is difficult to treat. Five-year survival for patients with localized disease is between 60 and 75 percent, according to the National Library of Medicine, but once the disease metastasizes and spreads beyond the confines of the kidney, five-year survival drops below five percent.

"The increases in incidence can't be explained by better detection methods alone," Dr. Copland says. "It's really daunting, and I think there are probably some environmental factors that are causing the disease to increase."

By coupling genomics technology with his background in molecular biology, Dr. Copland believes he can help halt or cure the disease by identifying combination therapies that target genes and other cellular components involved in renal cell cancer.

Using a technique known as genomic profiling, Dr. Copland is comparing tissue from renal cell tumors with normal kidney tissue from the same patient in order to identify genes that are, in essence, overactive or underactive in renal cell carcinoma. The data come from gene microarrays or "chips" which analyze the activities of each of the 25,000-plus genes in the human genome.

In his studies to date, those chips show that thousands of genes have a connection to renal cell carcinoma. That's where molecular biology comes into play. All of those genes can be grouped together by their functions in cells, which then makes it possible to identify "master genes."

These master genes control signal pathways that affect the behaviors of hundreds of genes and initiate the changes that make normal cells cancerous, Dr. Copland says. Therein lies the key to better therapies.

"I think we can go from a thousand or three thousand candidate genes to anywhere from five to 30 master genes and develop combination therapies that hit those targets," Dr. Copland says. "With this approach, we can halt the disease and begin to cure kidney cancer."

Thus far, Dr. Copland has identified one promising master switch for renal cell carcinoma, a gene called TGF beta, which influences the proliferation and spread of these dangerous cells. The task now is to further validate his findings and discover new pathways.

"We have all of the tools, and that's what's exciting," Dr. Copland says. "It's just a matter of dollars and putting people to work. Five years ago, we did not have the same ability to quickly make discoveries that will change the practice of medicine."

From the Bench to Bedside

An important tool for Dr. Copland and many other investigators is a vast storehouse of information, or data registry, that Mayo is building to support renal cell research. It includes a host of data on important clinical, demographic and lifestyle variables from renal cell cancer patients treated at Mayo's Jacksonville and Rochester campuses. More importantly, it also has an extensive biological component, which collects and stores high-quality tissue samples and blood and urine samples that are the building blocks of Dr. Copland's research.

Staffs at both the Rochester and Jacksonville are maintaining this registry, which currently contains information on thousands of patients. It's a valuable tool for a relatively rare cancer, says Alexander Parker, Ph.D. a clinical epidemiologist who is supervising the registry efforts in Jacksonville.

"Very few centers across the United States have the ability to build such a large registry for RCC because it's less common," says Dr. Parker, who recently chaired the renal cell carcinoma working group at the National Cancer Institute's workshop on Rare and Understudied Cancers in Boston. "A sizeable repository of well-characterized patient data and samples is vital for basic science investigations, but also for the follow-up validation studies we need to do in the clinic."

The registry's clinical potential is enormous. As it grows in size, its degree of detail will help physicians examine the entire natural history of renal cell cancer, from identification of potential screening tests to the design of more effective therapies. Physicians will also be able to use the registry to help patients make more informed decisions about treatment options.

"With renal cell carcinoma, we don't have an extensive amount of data because, again, it's less common," Dr. Parker says. "What we want is to be able to tell patients how the last 100 or so patients like themselves fared with a given treatment, what the side effects were, the risk of recurrence and so on. I compare it to investing your money. Think about all of the historical information you can get when you want to make an investment. Wouldn't you want the same type of data when making a decision about your cancer treatment? With the registry, we'll be able to empower patients and their physicians with more information."

Another Reason to Stop Smoking

The state of Florida has also taken note of the health risk that renal cell cancer represents, as well as the Jacksonville staff's potential for dealing with that concern. Drs. Copland and Parker are part of a four-investigator group that has received a $1 million grant from the James and Esther King Biomedical Research Program, a fund Florida established with proceeds from the state's lawsuit against tobacco companies to recover costs of care for tobacco-related disease.

The grant is the largest award possible under the fund, and with it Mayo is launching a project to further examine the connection between renal cell cancer and cigarette smoking. The investigators say the initial funding will allow them to collect important data, necessary for securing long-term support from the National Institutes of Health or a similar agency. And, in studying a common risk factor for the disease - cigarette smoking - they will learn about basic mechanisms and therapies that will help them improve diagnoses and treatments for all renal cell patients.

Promising Candidates

The program's components are:

• An epidemiological study led by Dr. Parker identifying the molecular mechanisms connecting smoking and renal cell cancer development.
• A laboratory study led by Panos Anastasiadis, Ph.D., discovering factors involved in renal cell metastasis.
• A laboratory study led by Dr. Copland evaluating new drug therapies used in combination to treat renal cell cancer.
• A clinical study led by psychologist Stephen Ames, Ph.D., identifying and evaluating psychosocial needs of renal cell patients following treatment.

The group's strength, Dr. Parker says, is its ability to investigate issues ranging across the entire spectrum renal cell carcinoma.

"It's the classic story of Mayo's strength in research," he says. "We have the ability to collaborate across many disciplines, and that means we can investigate a range of topics in renal cell research, from basic mechanisms all the way to patient care and even further into issues of quality of life. It's one of the biggest reasons we received the $1-million grant."