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May 24, 2005 • Volume 2 / Number 21 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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SpotlightSpotlight

Gene Discoveries Driving New Treatments for Kidney Cancer

It was 12 years ago that Drs. Marston Linehan, Berton Zbar, and colleagues from NCI's Center for Cancer Research (CCR) and elsewhere published a wonderful discovery. For many years they had studied families with Von Hippel-Lindau (VHL) syndrome, a rare, hereditary disease associated with benign tumors in multiple organs, but also with a form of the most common type of kidney cancer: clear cell renal cell carcinoma (RCC). The work paid off. They had linked VHL to a single gene on chromosome 3 - the first gene found to cause kidney cancer. Research done since that time has shown that 60 to 80 percent of patients with nonhereditary, or sporadic, RCC have a VHL mutation.

Drs. Linehan, Zbar, and their NCI colleagues have led the search for additional genes associated with other forms of kidney cancer, an effort that has taken on increasing importance "because of the steady, relentless increase in its incidence since the early 1970s," Dr. Linehan says.

More than 36,000 patients are now diagnosed with kidney cancer every year. Although patients diagnosed with early stage disease have a 95 percent 10-year survival, in advanced disease, the odds of surviving for 2 years are less than 1 in 5. The current treatments for advanced disease are interferon α and interleukin 2 (IL-2). Although IL-2-based therapy can result in complete responses and may be effective in up to 20 percent of patients, it takes specialized expertise to administer and can be accompanied by serious side effects.

Since the VHL gene discovery, the researchers have discovered two other kidney cancer genes (see table), all via studies of families with hereditary forms of kidney cancer conducted at the NIH Clinical Center.

Of these genes, VHL has been the most intensively studied. In particular, researchers have been able to map some of the intracellular signaling pathways affected by this gene. Part of VHL's function is to help suppress tumor growth. But when a mutation arises in VHL that either silences it or greatly decreases its activity, it can have a serious domino effect, explains Dr. William G. Kaelin, a leading expert on the molecular biology of kidney cancer at Dana-Farber Cancer Institute. First, there is an overproduction of a transcription factor called HIF. This, in turn, spurs the production of growth factors such as VEGF and PDGF, both of which fuel cancer cell growth.

So the discovery of these genes, says Dr. Ronald M. Bukowski, director of the Experimental Therapeutics Program at the Cleveland Clinic Taussig Cancer Center, has been significant because it has allowed kidney cancer researchers to more rationally investigate agents "that might affect the pathways these genes modulate."

Over the last few years, in fact, a number of early-phase clinical trials testing a variety of targeted agents against advanced kidney cancer have generated much excitement. Earlier this month at the ASCO annual meeting, for example, researchers from the University of California, San Francisco reported on the results of a 52-patient, phase II trial testing AG-013736, an experimental agent that targets VEGF and PDGF. At 1-year follow-up, the drug prevented disease progression in three-quarters of the patients.

Hopeful results also have been reported with the experimental agents SU011248 and sorafenib, as well as with targeted drugs approved by the Food and Drug Administration for the treatment of other cancers such as bevacizumab (Avastin), which targets VEGF, and erlotinib (Tarceva), which targets EGFR, also in the VHL pathway.

These findings have significantly changed the perception of kidney cancer, says Dr. Kaelin. "Kidney cancer was one of those solid tumors that medical oncologists always thought were pretty intractable in terms of chemotherapy," he notes. "So it's ironic that…there is now a lot of excitement about using targeted agents against it."

Gene Year Kidney cancer type, VHL 1993 Clear cell renal cell carcinoma, c-Met 1997 Hereditary papillary renal carcinoma, BHD 2002 Chromophobe renal carcinoma Dr. Bukowski argues that more than just the perception of this disease has changed. The findings from these trials are demonstrating "a changed paradigm for the treatment of [advanced kidney cancer]," he says. "Whenever you change how you approach the treatment of a disease, that's big news. That's clearly something that's happening with this illness."

Dr. Linehan's laboratory recently launched a phase II clinical trial of an antibiotic derivative called 17AAG for the treatment of kidney tumors in patients with VHL disease. Dr. Len Neckers, a principal investigator in the Urologic Oncology Branch, worked with NCI's Developmental Therapeutics Program and Cancer Therapy Evaluation Program to translate 17AAG to the clinic. This agent blocks a so-called molecular chaperone that protects HIF - and other critical signaling proteins - from damage when tissues are under the stress of low oxygen. In laboratory and animal models, 17AAG has shown impressive antitumor activity.

Over the more than 2 decades of conducting this research, Dr. Linehan recounts, the progress has been slow but steady.

"You can cure tumors in animals, you can cure them in the lab," he says. "We just have to go one step at a time. We're in this for the long haul, and I have hope that we'll get there."

By Carmen Phillips