PITTSBURGH, Jan. 11 - 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.
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.
As the only NCI-designated comprehensive cancer center in western Pennsylvania, UPCI is a recognized leader in providing innovative cancer prevention, detection, diagnosis, and treatment; bio-medical research; compassionate patient care and support; and community-based outreach services. UPCI investigators are world-renowned for their work in clinical and basic cancer research.
About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1997 and now ranks fifth in the nation, according to preliminary data for fiscal year 2008. Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see www.medschool.pitt.edu.