The drug bortezomib (Velcade), the first new treatment for multiple myeloma in a decade, is an example of how researchers in the Developmental Therapeutics Program (DTP) of NCI's Division of Cancer Treatment and Diagnosis (DCTD) are working with academic scientists, clinicians, and companies to facilitate the discovery and development of new and effective therapies for cancer.

Multiple myeloma is a malignant proliferation of plasma cells, of which there were an estimated 16,000 new cases in the United States in 2005. About 11,300 people died of the disease in 2005. Multiple myeloma is the second most common blood cancer, representing about 1 percent of all cancers.

Plasma cells typically make up about 1 percent of the cells in the bone marrow, but multiple myeloma tumor cells are overproduced and can account for 10 to 80 percent of the cells in the bone marrow, crowding out the normal bone marrow cells. The malignant myeloma cells remain mainly within the bone marrow, destroying bone and causing fractures and severe pain. Despite advances in therapy that improve the quality and length of life, the disease remains incurable. The survival rate for multiple myeloma patients is approximately 5 years.

In 1994, Dr. Julian Adams was working for a small biotech company when his research group discovered a potent inhibitor of proteasomes - structures within cells that act like garbage disposals, chewing up abnormal or damaged proteins so they cannot obstruct the normal workings of the cell. Inhibiting the proteasome causes proteins that would normally be destroyed to accumulate in a cell. Normal cells can typically withstand a reduction in protein breakdown; myeloma cells are more sensitive to the accumulation of these proteins and rapidly undergo cell death, or apoptosis.

Targeting the proteasome for cancer treatment was initially met with skepticism, and Dr. Adams needed to convince the scientific community that his idea was credible. He met with members of DTP in 1995 to discuss further development of bortezomib. DTP scientists agreed that the proteasome was a novel therapeutic target and that further research was needed to validate it as a viable target.

From 1995 to 1997, DTP supported cell line and animal studies that showed that bortezomib effectively inhibited the growth of cancer cells. As a result, in 1998 DCTD agreed to provide support for phase I testing of the compound.

"DTP improved the chance that bortezomib would be moved to clinical trials earlier through our efficacy and toxicology studies and the development of a stable formulation for the drug," said Dr. Joe Tomaszewski, DCTD deputy director. "Through the combined experience of DTP and the Cancer Therapy Evaluation Program (CTEP), we were able to facilitate the process of clinical trials approval and placement for this unique agent."

In 2000, phase I studies showed that multiple myeloma was susceptible to treatment with bortezomib and a phase II study quickly followed. These clinical trial results prompted the FDA to place bortezomib on a fast track for review. In 2003, bortezomib was approved for treatment of patients with myeloma who had not responded to at least two previous therapies. Bortezomib represents a new mechanistic class of cancer agent for treatment of multiple myeloma and is currently being investigated as a therapy in other types of cancer.

"CTEP has sponsored more than 60 early-phase clinical trials to evaluate the activity of bortezomib in a variety of solid tumors and hematological malignancies," said Dr. John Wright, of CTEP's Investigational Drug Branch. "We have found that bortezomib appears to be effective in the treatment of additional tumor types including non-Hodgkin lymphomas as well as lung cancers. Evaluation in these tumors and others is ongoing.

"This is a great example of how DTP played a pivotal role in preclinical testing of bortezomib, providing the drug for testing in collaboration with the clinical development program supported by CTEP to identify its effectiveness in tumor types other than multiple myeloma," Dr. Wright concluded.

By Lynette Grouse