Drug shows promise as new treatment for gut tumor

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.

The research was supported by grants from the National Institutes of Health, the American Cancer Society, the GIST Cancer Research Fund, the Life Raft Group, Deutsche Krebshilfe, the Virginia and Daniel K. Ludwig Trust for Cancer Research, UPCI and the Pennsylvania Department of Health.