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- Posted Wednesday September 18, 2013
Research team uncovers root cause of multiple myeloma relapse
Findings provide insights for new, targeted cancer therapies in clinical trials
SCOTTSDALE, Ariz. - Sept. 18, 2013 - Researchers have
discovered why multiple myeloma, a difficult to cure cancer of the
bone marrow, frequently recurs after an initially effective
treatment that can keep the disease at bay for up to several
years.
Working in collaboration with colleagues at Princess Margaret
Hospital in Toronto, researchers from Mayo Clinic in Arizona and
the Translational Genomics Research Institute (TGen) in
Phoenix were part of the team that conducted the study published in
the Sept. 9 issue of Cancer Cell.
The research team initially analyzed 7,500 genes in multiple
myeloma cells to identify genes which when suppressed made cancer
cells resistant to a common class of drugs called proteasome
inhibitors such as bortezomib or carfilzomib. Then, the team
studied bone marrow biopsies from patients to further understand
their results. The process identified two genes (IRE1 and XBP1)
that control response to the proteasome inhibitor and the mechanism
underlying the drug resistance that is the barrier to
cure.
The findings showed recurrence was due to an intrinsic resistance
found in immature tumor progenitor (mother) cells is the root cause
of the disease and also spawns relapse. The research demonstrates
that although the visible cancer cells that make up most of the
tumor are sensitive to the proteasome inhibitor drug, the
underlying progenitor cells are untouched by this therapy. These
progenitor cells then proliferate and mature to reboot the disease
process, even in patients who appeared to be in complete
remission.
"Our findings reveal a way forward toward a cure for multiple
myeloma, which involves targeting both the progenitor cells and the
plasma cells at the same time," says Rodger Tiedemann, M.D., a
hematologist specializing in multiple myeloma and lymphoma at
Princess Margaret. "Now that we know that progenitor cells persist
and lead to relapse after treatment, we can move quickly into
clinical trials, measure this residual disease in patients, and
attempt to target it with new drugs or with drugs that may already
exist."
"Some myeloma cells are too immature to be caught by the drugs and
thus hide underground only to reemerge later," says Keith Stewart,
M.B., Ch.B., Dean for Research at Mayo Clinic in Arizona and
contributor to the study. "This study has wide implications in the
search for a cure of this common blood cancer as this 'progenitor
cell' will have to be targeted."
Jonathan Keats, Ph.D., head of TGen's Multiple Myeloma Research
Laboratory, said: "This study, which leverages data generated at
TGen as part of the Multiple Myeloma Genomics Initiative, shows how
mutations acquired by multiple myeloma tumors can make a tumor
resistant to specific therapies and highlights the importance of
TGen's precision medicine approaches."
Dr. Tiedemann says: "If you think of multiple myeloma as a weed,
then proteasome inhibitors are like a goat that eats the mature
foliage above ground, producing a remission, but doesn't eat the
roots, so that one day the weed returns."
The study - Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts
Mediate Therapeutic Proteasome Inhibitor Resistance in Multiple
Myeloma - was funded by the National Cancer Institute, Multiple
Myeloma Research Foundation, Leukemla and Lymphoma Society and
Canadian Cancer Society, the Arthur Macaulay Cushing Estate and The
Princess Margaret Cancer Foundation.
Dr. Tiedemann is the Molly and David Bloom Chair in Multiple
Myeloma Research, at the University of Toronto, Dr. Stewart is the
Anna Maria and Vasek Pollack Professor of Cancer Research at Mayo
Clinic. Dr. Keats is an Assistant Professor in TGen's Integrated
Cancer Genomics Division.
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About TGen
Translational Genomics Research Institute (TGen) is a Phoenix,
Arizona-based non-profit organization dedicated to conducting
groundbreaking research with life changing results. TGen is focused
on helping patients with cancer, neurological disorders and
diabetes, through cutting edge translational research (the process
of rapidly moving research towards patient benefit). TGen
physicians and scientists work to unravel the genetic components of
both common and rare complex diseases in adults and children.
Working with collaborators in the scientific and medical
communities literally worldwide, TGen makes a substantial
contribution to help our patients through efficiency and
effectiveness of the translational process. For more information,
visit:www.tgen.org.
Press Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
[email protected]