Fall 2007 - International Waldenstrom's Macroglobulinemia ...

More Funds, More Research, cont from page 1
New Classes of Drugs to Treat Waldenstrom’s
Macroglobulinemia - In research sponsored by the IWMF,
Dr. Constantine Mitsiades at Dana-Farber has identified
several chemical agents which are effective in the treatment
of WM; those agents are the foundation of research currently
conducted by Dr. Steven Treon’s group at the Bing Cancer
Lab at Dana-Farber.
The agents studied by Dr. Mitsiades are the proteosome
inhibitor PS-341 (bortezomib), thalidomide derivatives
(pamilidomideor, Actimid) and heat shock protein inhibitors
(hsp90). His work focuses on the molecular basis of their anti-
WM activity and shows that each of these agents interferes
with the signaling functions associated with apoptosis,
proliferation of WM cells, and the activation of genes that
cause increased production of WM cells. Dr. Mitsiades also
demonstrated that these agents enhance the activity of other
anti-cancer agents.
Factors Regulating Immunoglobulin-producing B-cells
in Patients With Waldenstrom’s Macroglobulinemia - Dr.
Stephen Ansell of the Mayo Clinic in Rochester, Minnesota,
had an initial IWMF grant to study the activity of B-lymphocyte
stimulator (BLyS) in regulating the proliferation of WM cells.
To date, progress has been made in showing which chemical
parts of BLyS effect WM cell growth, and several variations of
BLyS have been synthesized and are being studied for activity.
Dr. Ansell also demonstrated that other cytokines (proteins)
cause the growth and death of WM cells. As a second phase
of his project he proposed a study focused on these cytokines
and received funding from the IWMF. He has already
successfully shown that cytokines previously known to be
active in vitro are also active in vivo. Moreover, his work has
determined that IL-6 in combination with BLyS increases the
production of WM cells and that IgM production increases in
the presence of the connective (stromal) cells in tissues.
Molecular and Functional Sequelae of the P13K Pathway
in Waldenstrom’s Macroglobulinemia - Dr. Irene Ghobrial
of Dana-Farber is conducting a clinical trial in which patients
are treated with perifosine, which has been shown to inhibit
a molecular pathway stimulating WM cell growth. The trial
has seen some success with 25 patients being treated. While
11 patients dropped out of the trial for various reasons, the
14 patients remaining showed no sign of disease progression
after two treatment cycles. Six of the 14 have shown a
reduction in IgM levels.
The IWMF gave Dr. Ghobrial a research grant for laboratory
work to identify the pathways signaling to WM cells and to
test various agents for disrupting those signaling pathways.
Dr. Ghobrial’s group is in the process of testing combinations
of perifosine, bortezomib and rituximab.
Genetic Characteristics of Waldenstrom’s
Macroglobulinemia - Dr. Linda Pilarski of the University
of Alberta and the Cross Cancer Institute received an IWMF
research grant to study the hypothesis that genetic factors
related to the hyaluronan synthase (HAS1) cause people to
contract various blood cancers. Her studies demonstrate that
mutations of the HAS1 gene can cause WM or MM. Under
the grant she is conducting detailed laboratory work to
determine which mutations are associated with each disease.
By testing people before they contract cancer and identifying
the mutations of the HAS1 gene, Dr. Pilarski believes that
predictions can be made regarding the type of cancer they
will develop and how severe the effects will be.
Comprehensive Studies Into the Genetic Basis and
Pathogenesis of Waldenstrom’s Macroglobulinemia - Dr.
Steven Treon’s group at the Bing Center for WM at Dana-
Farber received a four-year research grant to study the genetic
and molecular origin of WM. Three main areas of research
are being funded by this grant. The first area examines
possible genetic predispositions to WM. Studies aimed at
characterizing the blood and cheek cells of both WM and
healthy patients have reinforced previous findings that some
ethnic characteristics (e.g. Ashkenazi) increase the risk of
WM. In addition Dr. Treon’s group has demonstrated that
in family members of WM patients there is a trend revealing
significant irregularities in serum immunoglobulin and
cholesterol levels.
The Dana-Farber group also studied the sequences of various
genes that could be involved in sending messages controlling
WM cell growth and death. Finally, in collaboration with
researchers from the University of Arkansas, gene expression
profiling was also extensively used at Dana-Farber. By
considering which genes were expressed and which
suppressed, the group was able to separate WM patients from
the normal population. WM patients were found to have a
distinct molecular signature, the implications of which need
further elucidation.
Dr. Treon’s second project deals with alterations in the TACI/
TRAF signaling pathway and their ability to predispose
a patient to WM and decreased levels of IgA and IgG.
Mutations were found in TACI which correlated with lower
levels of IgA and IgG. Additional studies are underway to
expand these results by testing more patients, their extended
families, and healthy donors.
The third area of research attempts to determine the
mechanisms which permit the expansion of cancer cells in
the bone marrow of WM patients. The major finding of this
work is that WM cells tend to secrete a soluble protein labeled
sCD27 which is elevated above the level seen in healthy
subjects. These cells were demonstrated to stimulate CD40L
and APRIL, two factors that control growth and survival of
WM cells. Additional work is required to substantiate these
findings.
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