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“A drug that is already an approved therapy for some cancers also might be an effective secondary treatment for a rare tumor of the gastrointestinal tract, according to a team led by researchers from the University of Pittsburgh Cancer Institute (UPCI). The findings, based on experiments using cell cultures, were published in the Jan. 1 issue of Cancer Research.

Bortezomib, or Velcade, is used to treat multiple myeloma and certain lymphomas, said Anette Duensing, M.D., assistant professor of pathology, University of Pittsburgh School of Medicine, an investigator in the Cancer Virology Program, UPCI, and senior author of the study. It works in part by preventing the degradation of certain proteins, which when elevated, induce apoptosis, or programmed cell death, in the cancerous cells.

The researchers suspected that activity could provide an effective way of killing gastrointestinal stromal tumor (GIST) cells. Patients with these tumors are typically treated with imatinib, or Gleevec, and most do very well initially, but complete responses are rare, Dr. Duensing said. There is a need for second- and third-line agents to treat patients whose tumors have become resistant to imatinib. Most GIST patients eventually develop such resistance.

In experiments using a GIST cell line, the researchers found that administration of bortezomib led to cancer cell death through two mechanisms. First, the drug increased the production of a protein called H2AX, which promotes cellular apoptosis. Second, and unexpectedly, the drug also suppressed the cancer cells' production of an enzyme called KIT. Primary mutations in KIT initiate GISTs, and secondary KIT mutations are the driving force behind cancer progression as well as drug resistance in these tumors, Dr. Duensing noted. Importantly, bortezomib also was active against imatinib-resistant GIST cells.

"This is intriguing because resistance to imatinib seems to permit a small pool of quiescent cancer cells to survive," she explained. "But bortezomib eradicates KIT production, so it might be able to rid the body of the remaining tumor cells."

Bortezomib is not presently an appropriate first-line therapy for GIST, she cautioned. But the current findings support moving forward to a clinical trial in appropriate GIST patients to assess its benefits and risks as a secondary treatment.

The research team includes lead author Sebastian Bauer, M.D., and Thomas Mühlenberg, University of Essen Medical School, Germany; Jonathan A. Fletcher, M.D., Brigham and Women's Hospital and Harvard Medical School; Brian P. Rubin, M.D., Ph.D., Lerner Research Institute and Taussig Cancer Center, Cleveland; and Stefan Duensing, M.D., and other researchers from UPCI and the University of Pittsburgh School of Medicine.


From Marina: 1/12/2010

""First, the drug increased the production of a protein called H2AX, which promotes cellular apoptosis. Second, and unexpectedly, the drug also suppressed the cancer cells' production of an enzyme called KIT.""

Velcade clogs up something called the proteasome which acts as the cellular garbage disposal.

You can think of proteins as following an assembly line process...proteins are made...proteins do jobs for the cell...old proteins are destroyed in the proteasome. The amount of a protien that is available in a cell depends on the rate at which the protein is made minus the rate in which the protein is destroyed (by the actions of the proteasome).

Inhibiting the proteasome garbage disposal by Velcade may allow for the build up of certain proteins in the cell beyond their normal levels. An accumulation of tumor suppressors could in theory affect how much other genes are used to make cancer signaling proteins: such as a slow down of making KIT (a gas pedal for GIST), or an acceleration of making p53 (a brake on GIST), and so on.

Velcade is already approved for multiple myeloma, and was pioneered by Julian Adams of Infinity when at Millenium. Multiple myeloma cancer cells highly over express something called the M protein, and secret it--so much M protein is made that it can damage the kidneys. Probably Velcade causes multiple myeloma cells to choke on their own waste of vastly over produced M protein.