Researchers at Mayo Clinic Cancer Center, in cooperation with industry partners, have, for the first time, identified tumor specific alterations in the cellular pathway by which the multiple myeloma drug bortezomib (Velcade) works, and they have identified nine new genetic mutations in cancer cells that should increase a patient's chance of responding to the agent.
The investigators say these findings, presented Sunday, Dec. 10, at the 2006 American Society of Hematology Annual Meeting in Orlando, may help physicians tailor treatment to patients with multiple myleoma, a difficult-to-treat cancer of plasma cells that is the second most common blood cancer in the United States.
"Bortezomib seems to work in about one-third of patients who use it, but we have not been able to predict which ones," says the study's lead author, Leif Bergsagel, M.D., a hematologist at Mayo Clinic Arizona. "We now have identified a group that will likely respond because these nine mutations seem to be present in at least 25 percent of newly diagnosed patients.
"Now that we know the pathway the drug targets, and genetic mutations within this pathway that make patients respond better, we are working on a simple way to select those patients who are the best candidates for use of bortezomib," says Dr. Bergsagel.
In 2003, after only a four-month review, the Food and Drug Administration (FDA) approved use of bortezomib in patients who have failed other treatments for multiple myeloma. Later studies showed it lengthened survival by as much as six months. The drug was the first approved in a new class of agents known as proteasome inhibitors. Proteasomes are large protein groups inside cells that break down other proteins. Agents that inhibit the proteasome cause a buildup of proteins that affect many signaling cascades (various necessary biological processes). Bortezomib was initially thought to exert its activity by disrupting one of two known NF-êB (Nuclear Factor kappa B) pathways which keep cancer cells from self destructing the first-discovered, or canonical, NF-êB pathway.
But through extensive genetic examination of 42 unique multiple myeloma cell lines and tumor samples taken from 68 patients, the investigators defined multiple genetic mutations in the other NF-êB pathway, the so-called non-canonical pathway. "These mutations make the tumor more dependent on that pathway, and consequently more susceptible to bortezomib treatment," said senior author Rafael Fonseca, M.D., also at Mayo Clinic in Arizona.
"Identifying these mutations in patients will help us decide who should be treated with bortezomib, probably as an initial therapy," he says. The researchers are developing a test to check for activation of the non-canonical NF-êB pathway in patients.
Now that the mutations have been identified, drug designers may be able to fashion new therapies that are more specific to these genetic alterations and, therefore, less toxic,
Dr. Bergsagel says. "These mutations represent good targets for drug development," he says.
Other Mayo researchers involved in this study included Marta Chesi, Ph.D.; Scott Van Wier; Jonathan Keats, Ph.D.; Michael Sebag, M.D., Ph.D.; Wee-Joo Chng, M.D.; Roelandt Schop, M.D.; Homer Fogle III; Yuan Xiao Zhu Ph.D.; Chang-Xin Shi, Ph.D.; Tammy Price-Troska; Gregory Ahmann; Kim Henderson; Philip Greipp, M.D.; Angela Dispenzieri, M.D.; Keith Stewart, M.D.; and Rafael Fonseca, M.D. They collaborated with researchers John Carpten, Ph.D.; Angela Baker, Ph.D.; Tae-Hoon Chung, Ph.D.; Michael Barrett, Ph.D.; and Catherine Mancini from TGen, Phoenix, Ariz., and Laurakay Bruhn, Ph.D. from Agilent Labs, Santa Clara, Calif.
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