Posted: May 5, 2011

RESEARCHER PROFILE: A Surgeon's Search for the Kidney Cancer Gene

Catherine Evans

Image: Dr. Marston Linehan

In the early 1980s, patients with advanced kidney cancer were all dying. Other than surgical removal of tumors, not much could be done for kidney cancer patients whose disease had spread. Hundreds of experimental drugs had been tested and failed.  

Now, says Marston Linehan, M.D., the National Cancer Institute’s (NCI) Chief of Urologic Surgery, things are different. Recently identified therapeutic approaches at the National Institutes of Health (NIH), using drugs that target the pathways of kidney cancer genes, have led to dramatic responses in some patients. The path to the development of these new kidney cancer drugs started with a search for one mutation in a sea of billions of DNA base pairs. However, when Dr. Linehan and his colleagues started searching for the gene responsible for kidney cancer, they never expected that it would turn into the search of a lifetime.

Dr. Linehan began work as a urologic surgeon at the NIH in 1982, trying his best with the limited options available to treat kidney cancer patients. Around that time, scientists began to realize that a potential approach to combating cancer was to hit it at its roots. The roots of these cancers are the altered genes that allow the cells to grow out of control. If they could find the gene alterations that resulted in unregulated cell growth, future drugs could be designed to target these cancer gene pathways, potentially halting the cancer’s deadly forward march.  

Dr. Linehan grew tired of seeing drug after drug fail in his patients. He and his colleague, Berton Zbar, M.D., decided to look for the kidney cancer gene. “People said to me, ‘What are you thinking?  You’re a urologic surgeon,’” he says. Despite the uncertainties, he forged ahead.

The Search Begins

Using samples from the tumors he took from his patients, he and his colleagues showed that there was a consistent loss of a segment of chromosome three in the kidney cancers. The Human Genome Project did not yet exist, so they had no reference genome to guide them. After extensively mapping the area of chromosomal deletion, he and his colleagues came to the realization that if they worked “13 hours a day, six days a week, with the tools we had available to us in the mid 1980s, we could definitely find the cancer gene at this location within 54 ½ years.” It was time for a new approach.

Dr. Linehan and his colleagues began talking with other scientists about a better way to find his gene. Instead of studying unrelated individuals with non-inherited kidney cancer, the colleagues suggested, why not use a shortcut method and study families with a rare, inherited form of kidney cancer? It would be easier to find a defective gene that had been passed down to relatives rather than a randomly mutated gene in unrelated individuals. And it was possible that this gene also played a role in the common form of non-inherited kidney cancer.

The new approach paid off. Dr. Linehan and his colleagues gathered families from around the country who had a hereditary cancer syndrome called Von-Hippel Lindau (VHL), taking samples of their blood and their kidney tumors. To date, Dr. Linehan’s group has studied about 300 families, totaling almost 700 patients. In the spring of 1993, Dr. Linehan, Dr. Zbar and a third colleague, Michael Lerman, M.D., Ph.D., finally narrowed down the region on chromosome three to a gene they named VHL, which was the sixth cancer gene found. VHL, they soon discovered, was not only responsible for the inherited Von-Hippel Lindau kidney cancer, it was also the primary gene for the common, non-hereditary form of clear cell kidney cancer.  

VHL is a tumor suppressor that normally functions to keep cells from growing out of control--this function is lost when the gene is mutated. The scientists conducted laboratory experiments to further examine the mechanisms by which the loss of VHL wreaked havoc in kidney cells. Their findings and those of others working on this pathway provided the foundation for the subsequent development of six FDA-approved drugs that target the VHL gene pathway in patients with advanced kidney cancer. These drugs are different from the drugs that had failed in the past: instead of being lethal to all growing cells, healthy or not, they target the specific pathway that causes this type of cancer. Instead of giving a broad swipe, the new drugs deliver a direct punch.   

From Findings to Treatment

After VHL, a number of other kidney cancer gene discoveries followed, several of which Dr. Linehan’s group found. They continued studying families with rare, inherited types of kidney cancer. In each case, after they found the defective gene responsible for the cancer, he and colleagues worked to figure out its mechanisms within cells in order to build a foundation for treatments. They are currently testing several of these potential drugs in clinical trials, some of which have yielded promising results.

A patient of Dr. Linehan’s, a woman with a hereditary kidney cancer that had spread, received one of the new drug combinations. Four other members of her family with the disease had already died. Now, 4 ½ years after Dr. Linehan’s colleague, Ramaprasad Srinivasan, M.D., Ph.D., initiated the treatment, she is cancer free. “She’s had a complete response for 3 ½ years. She developed a new tumor in the kidney, which we removed, and now we can’t detect anything,” Dr. Linehan says.  

As remarkable as some patients’ responses have been, clinicians must still temper their optimism with caution. According to Dr. Linehan, many of the patients who initially respond well to the experimental drugs later relapse. “We need better drugs, no question about it,” he says. “But we also need to know much more about the genetic basis of kidney cancer.”  

The Path Ahead

While cancer researchers have gained an incredible amount of knowledge about kidney cancer, they have simultaneously found that it is much more complicated than anyone had anticipated. “When we started, kidney cancer was easy to understand: it was a single disease,” Dr. Linehan remembers. “Now we know, of course, it’s not. It’s a number of different types of cancer, of different histologies and different clinical courses. Some will grow faster, some slower, some will respond differently to therapies and they’re caused by different genes.”

So the search for one gene has expanded into a search for many genes and their many alterations. The Cancer Genome Atlas’s (TCGA) large-scale approach of annotating all the gene changes involved in kidney cancers is a way to tackle the mountain of questions left over from research projects like Dr. Linehan’s. And he has been happy to help out, playing a pivotal role in TCGA as a provider of kidney tumors and a contributor of kidney cancer expertise.

He has been impressed with the team members’ dedication to the TCGA kidney cancer effort. “Everyone always had the same emphasis: what’s the best science? Nobody was thinking about their [own] work, they were thinking about the science for this important project,” he recalls.  

Dr. Linehan and others are excited about TCGA’s potential, despite the fact that the road to a complete atlas is bound to be a long one. However, Dr. Linehan believes the journey is worth it. “This could take us into an entirely different direction of therapy and open up whole new avenues for treatment,” he says. “I’m sure the work that comes out of this is going to keep a whole generation of scientists and physician scientists busy working to develop new approaches for therapy. So I can’t think of a better use of resources than this project, to be honest with you. I can’t think of anything that has more potential to affect how we think about these cancers than this project. I can’t think of anything.”