Scientific & Clinical
2008 imf researcH grant recipients announced
The recipients of the 2008 IMF Research Grant awards were announced at the gathering of the Foundation's
Scientific Advisors, held at the 49th annual meeting of the American Society of Hematology.
Since1995,theIMF'sresearchprogramhasbeenfundingtheworld's 2008 Brian D. Novis Junior Research Grants
most promising clinical investigators in order to further research
"Role of XBP-1 in Drug Resistance of Multiple Myeloma"
into better treatments, management, prevention and, ultimately, a cure
for
multiple
Silvia Ling, MD, MBBS,
myeloma. The
FRCPA, FRACP
2008 IMF grant
Centenary Institute
awardpresenta-
of Cancer Medicine
tions took place
and Cell Biology
during the 49th
Newton, NSW, Australia
annual meeting
Proteasome inhibitors are an effec-
and exposition
tive new approach to treating
of the American Society of Hematology (ASH). Susie Novis (president and
multiple myeloma. Some 50-60%
co-founder of the IMF), Dr. Brian G.M. Durie (chairman and co-founder of
the IMF), and Dr. Robert A. Kyle (chairman of the IMF Scientific Advisory
of myeloma patients respond to
Board) were on hand to present the awards.
bortezomib (VELCADE®), the first drug of this class to be approved for
clinical use. It is striking that its relevant mechanism of action in myeloma
The IMF grants are funded by donations from private individuals. Junior
cells remains unknown. Proteasome inhibitors have numerous biological
investigators receive funding in the amount of $40,000. Senior inves-
effects but none of them had been shown to predict response. The causes
tigators are funded at $80,000. While IMF research grants traditionally
of bortezomib resistance were also unknown. The first part of the study
support one-year projects, two of this year's recipients are receiving con-
conducted by Dr. Ling showed that levels of XBP-1, a regulator of the
tinued funding based on the results of the investigators' work in 2007.
unfolded protein response, predict response to bortezomib in vitro and in
Over the years, the IMF research grant program has produced significant
a small cohort of patients. Dr. Ling and colleagues have also made myelo-
results that have both increased the overall understanding of the disease
ma cell lines resistant to bortezomib and showed that they downregulated
and have benefited myeloma patients by improving treatment options. We
XBP-1 and other genes of the unfolded protein response. Dr. Ling's goals
are certain that the work of the recipients of the 2008 IMF research grants
are now to test the utility of XBP-1 as a marker of response to bortezomib
will contribute significantly to the field of myeloma.
in a larger number of patients, and to characterize the bortezomib-resis-
2008 Brian D. Novis Senior Research Grant
tant cell lines, in terms of molecular mechanisms and cross-resistance to
other drugs. These studies should help clinicians to optimize treatment
"Hedgehog Signaling in Myeloma Cancer Stem Cells"*
strategies for myeloma, and aid the development of improved drugs.
William Matsui, MD
Assistant Professor of Oncology
"A novel CCR1 Inhibitor for the Treatment of OBD
Division of Hematologic Malignancies
in Multiple Myeloma"**
The Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Sonia Vallet, MD
Baltimore, MD
Massachusetts General Hospital
Boston, MA
Cancer stem cells are thought to be respon-
Osteolytic bone disease (OBD) is a fre-
sible for the growth and progression of many
quent complication of multiple myelo-
human tumors including multiple myeloma.
ma. It is characterized by reduced
Dr. Matsui's laboratory has focused on study-
bone formation and increased bone
ing myeloma stem cells and recently found
resorption, resulting in increased risk
that the Hedgehog signaling pathway, normally active during embryonic
of fractures. Myeloma cells secrete
development, regulates the growth and maturation of these cells. With the
several cytokines that promote bone
support of the 2007 IMF Brian D. Novis Senior Research Grant, Dr. Matsui
resorption by interacting with specific receptors. MLN3897 (Millennium
and his laboratory have found that Hedgehog signaling is abnormally acti-
Pharmaceuticals, Cambridge) is a novel, orally available inhibitor of the
vated within cancer stem cells isolated from some, but not all, patients with
cytokine receptor CCR1. It has a safe toxicity profile, and its anti-inflam-
myeloma. In addition, it appears that myeloma stem cells can be inhib-
matory properties are under study in rheumatoid arthritis and multiple
ited when Hedgehog signaling is blocked. With the support of the 2008
sclerosis patients. Studies conducted by Dr. Vallet and her colleagues have
IMF Brian D. Novis Senior Research Grant, Dr. Matsui and his colleagues
shown that MLN3897 blocks the formation and activity of osteoclasts cells,
will continue these studies and determine whether Hedgehog signaling
resulting in decreased bone resorption. Importantly, they have also shown
becomes "turned on" during myeloma relapse and progression, as well
that MLN3897 reduces myeloma cell growth by inhibiting the growth and
as study whether novel agents that block Hedgehog signaling are effective
against myeloma cancer stem cells.
Continues on Page 8
800-45-CURE(87)
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Scientific & Clinical
GRANT RECIPIENTS -- continued from page 7
survival advantage conferred on them by the bone marrow microenviron-
cells without damaging normal cells. Cell death occurred rapidly, without
ment. Therefore, MLN3897 may be an effective treatment for osteolytic
the need for exogenous immunological effectors. Furthermore, the mAbs
bone disease in myeloma patients. Dr. Vallet will study these potential
were also active and therapeutic in vivo in xenograft mouse models of
anti-osteolytic and anti-myeloma effects of MLN3897 in an in vivo model.
myeloma. In the proposed project, Dr. Yang and colleagues will develop
Data generated from these studies will provide the framework for clinical
strategies to enhance the antimyeloma efficacy of mAbs. These strategies
trials in myeloma patients with bone disease.
will include sensitizing myeloma cells to mAb-mediated apoptosis with
interferon-, combining chemotherapy drugs with mAbs to synergize
"Targeting Multiple Myeloma with Nanobodies:
antimyeloma effects, and using immunological effectors to enhance mAb-
study in the 5TMM model"
induced myeloma cell apoptosis. Collectively, these studies will lead to
Karin Vanderkerken, PhD
a better understanding of the role of anti-2M mAbs in myeloma, and
Vrije Universiteit Brussel
will enable the development of a more potent therapeutic antibody to be
Brussels, Belgium
translated into clinical application.
Dr. Vanderkerken's project investi-
2008 IMF Japan Aki Award***
gates using nanobodies in targeting
"Establishment of Models for Multiple Myeloma"
multiple myeloma. Nanobodies are
single-domain antigen binding enti-
Yutaka Okuno, MD, PhD
ties, roughly four times smaller than a
Department of Hematology
classical antibody fragment, and very
Kumamoto University
stable. Nanobodies will be generated
Kumamoto, Japan
after immunizing camels with a myelo-
The transcription factor PU.1 is essential
ma-specific antigen, followed by the production of these nanobodies in
for myeloid and B-cell development. In
vitro using different molecular biological techniques. The biodistribu-
his recent research study, Dr. Okuno
tion of the nanobodies will be assessed by labeling the nanobodies with
and colleagues found that PU.1 is down-
99mTc, injecting them in myeloma bearing mice, and monitoring in vivo
regulated in the majority of human
by a combination of gamma tomography and CT imaging. When proven
multiple myeloma cell lines and a sub-
to target the myeloma cells with a high specificity, these nanobodies will
set of myeloma patients, in contrast to
be coupled to various molecules and/or compounds to treat the myeloma
relatively high expression of PU.1 in
cells locally, thereby minimizing unwanted toxic side effects.
normal plasma cells. Conditional expression of PU.1 in myeloma cell
lines induced complete growth arrest and apoptosis. Patients in this low
"Targeting 2-Microglobulin for Induction
PU.1 expression subset may have a poor prognosis. It is possible that
of Tumor Cell Apoptosis in Myeloma"
down-regulation of PU.1 might induce unregulated plasma cell growth
Jing Yang, PhD
that leads to myeloma. Therefore, Dr. Okuno and colleagues are generat-
MD Anderson Cancer Center
ing conditional knockout mouse models that lack PU.1 expression only
Department of Lymphoma
in plasma cells. Those mice would help understanding the role of PU.1
and Myeloma
down-regulation in myeloma cells. This may represent a new therapeutic
Houston, TX
strategy for treatment of myeloma patients.
Multiple myeloma disease relapses despite
the most aggressive treatment available
* This project has received second-year funding.
today. Successful targeted monoclonal anti-
** This project has been funded in the name of Jeffrey Stafford
bodies (mAbs) therapy has had clinical
(by the WAMP Swim-a-Thon member fundraising event organized
efficacy in lymphomas (anti-CD20 mAbs)
by Mr. Stafford's children) and in the name of Mark Rubin (by the
and in breast cancer (anti-EGFR mAbs).
Music Against Myeloma member fundraising event organized by son
Unfortunately, due to the lack of an available therapeutic antibody in
Slava Rubin).
clinical trails, no such approach has yet been developed for myeloma.
***This annual myeloma research grant was instituted in 2002
The overall goal of Dr. Yang's research project is to develop more effective
by IMF Japan in memory of its founder, Aki Horinouchi.
therapeutic mAbs to eradicate myeloma cells for clinical study. Dr. Yang
and her colleagues recently made a novel and exciting discovery that
The IMF offers grants to doctors and researchers working in the field
mAbs specific for human 2-microglobulin (2M) had remarkably strong
of myeloma. To apply for 2009 funding, please download a grant
apoptotic activity both in established myeloma cell lines and in primary
application from the IMF website www.myeloma.org or call
myeloma cells from patients. These mAbs selectively targeted and killed
800-452-CURE (2873) to request an application to be mailed to you.
myeloma cells in coculture with a large amount of normal hematopoietic
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www.myeloma.org