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Staff scientist Avi Ashkenazi and director of molecular oncology Vishva Dixit are discovering ways to harness the biological mechanism of apoptosis, or programmed cell death, in their fight against cancer.

Perhaps nowhere in Genentech are the intensity and drive to succeed more apparent than in the research labs. Science has been the foundation of Genentech, and the company's commitment to the pursuit of excellent science remains foremost. Its 400 scientists are among the top in their fields, publishing 250 to 275 papers annually — a rate unmatched in the biotech and pharmaceutical industries. As one scientist put it, "At Genentech, we're encouraged to act on promising leads, follow our intuition and test our hypotheses. This enables great science versus formula."

Basic Science as a Powerful and Practical Tool

Scientists Vishva Dixit and Avi Ashkenazi of Genentech's molecular oncology department are world-renowned leaders in the study of apoptosis, the mechanism by which cells self-destruct. Both researchers are intent on uncovering ways to use this built-in regulatory process to fight cancer. "Essentially, our philosophy is to discover biological pathways, understand how they operate and then put them to work for us," says Ashkenazi. This strategy has proved quite productive — with one molecule in development and several other promising genes in earlier stages of research.

Apoptosis is a natural regulatory program for suicide that exists in all cells, including cancer cells. Its purpose is to eliminate damaged or unneeded cells from the organism; however, in cancer cells this self-regulation program is silenced, allowing tumors to survive and grow. Dixit and Ashkenazi are finding new ways to activate the apoptosis machinery in cancer cells as a means of attacking tumors.

A major breakthrough for Ashkenazi's team came several years ago when they discovered the Apo2L/TRAIL gene, which encodes for a protein that can trigger the apoptosis machinery in certain cells. They found that their recombinant version of this protein could effectively kill tumor cells, while sparing normal ones. Further investigation led to the identification of the protein's receptors and the revelation that these "death receptors" can activate the dormant suicide machinery of cancer cells. Concurrent with Genentech's work in this area, scientists at Immunex Corporation had identified and were studying the same gene. To facilitate rapid development and maximize the complementary strengths of both companies, a collaborative agreement was formed in 1999. Today, Apo2L/TRAIL is in Genentech's development pipeline, where it will be evaluated for efficacy in a number of solid-tumor cancers.

Having a research focus on apoptosis has helped keep Genentech's molecular oncology researchers out front and ahead of the competition. As Dr. Dixit puts it, "The pace of our apoptosis research has accelerated dramatically over the past two years. Every day we learn something new about this process and how to take best advantage of it therapeutically."

A Novel Approach to an Age-Old Disease

In addition to oncology and cardiovascular medicine, Genentech scientists conduct research in a range of "opportunistic" areas with significant unmet medical needs. Cell biologist Ellen Filvaroff, Ph.D., is currently leading efforts to address an unmet need of monumental proportions: osteoarthritis (OA). Filvaroff is tackling the problem on a number of fronts, working to unravel the biology of human joints while also investigating proteins that may have beneficial effects on diseased joints.

Osteoarthritis affects up to 13 percent of the U.S. adult population — costing the country over $50 billion each year in lost earnings and medical care. Current treatments include physical therapy, analgesics, intra-articular steroid injections and, in the most severe cases, surgery. To date, no drug has been shown to slow or reverse the progression of the disease. The need (and the market) for such a therapy is both vast and growing. OA is one of the most prevalent chronic conditions in people over 65 (a group poised to expand as baby boomers age) and is among the leading causes of disability in adults.

Scientist Ellen Filvaroff (center), along with research associates Min Bao and Liping Cai, is searching for new ways to slow down osteoarthritis.

"My work," says Filvaroff, "is focused on the structural aspects of OA." To this end, she is investigating a protein that appears to have a positive impact on articular cartilage, because degeneration of this tissue is a central feature of OA. Says Filvaroff, "We think that a factor that can delay or reverse cartilage breakdown will likely slow or halt progression of disease." So far, various formulations of this protein have been tested in vitro and in vivo, and Filvaroff has forwarded her findings to Genentech's marketing department to gauge interest in such a therapy among orthopedic surgeons.

Filvaroff's experiences typify Genentech's uniquely nurturing, integrated approach to scientific discovery. When she arrived three years ago, she brought an expertise in the musculoskeletal system and was offered the opportunity to choose an area of focus to pursue. She thought immediately of OA. "I know a number of people with this debilitating disease," she says. "I thought, "This is a disease that Genentech should be studying — with its advanced technology and collection of cloned genes.' " As Filvaroff began her research, colleagues offered to share their expertise, as well as pertinent findings from their own studies. This, along with access to Genentech's integrated network of databases and resources, may help Filvaroff find the answers she's looking for and provide osteoarthritis patients with a much-needed therapy.