By John C. Byrd, MD
2009-09-01
Dr.
Byrd indicated no relevant conflicts of interest.
Xu Y, Li J, Ferguson GD, et al. Immunomodulatory
drugs reorganize cytoskeleton by modulating Rho GTPases. Blood. 2009. [Epub
ahead of print]
The
immune-modulating therapeutic agent lenalidomide is a broadly active
therapeutic agent for a variety of hematologic malignancies including multiple
myeloma, del(5q-) myelodysplastic syndrome, acute myeloid leukemia,
non-Hodgkin lymphoma, Hodgkin disease, and chronic lymphocytic leukemia. This
has prompted considerable interest in developing third-generation immune
modulation agents, such as pomalidomide. Several of these are currently in
clinical trials for multiple myeloma where promising responses have been
observed. One of the perplexing things about this class of medications is the
diverse potential mechanism(s) of action, including immune effector cell activity
enhancement, tumor microenvironment interference, and direct tumor-directed
apoptosis. To date, very few studies have identified pathways upon which this
class of agents acts or if the different agents have divergent mechanisms of
action. In this paper, Drs. Xu and Xie and their colleagues from Celgene, demonstrated
that pomalidomide activates monocytes by activating specific small-molecular-weight
G-proteins, RhoA and Rac1, with subsequent enhancement of F-actin formation,
stabilization of microtubules, and increase in cell migration. When examined in
T cells, similar findings were observed with both pomalidomide and
lenalidomide. RhoA activation with lenalidomide was tied to T-cell production
of the “general officer” cytokine IL-2 that, in many prior publications, was
shown to be required for lenalidomide-induced activation of other immune
effector cells. This activation was not direct, thereby providing a lead for
other investigators to pursue just how this is occurring in future
investigations of this novel class of drugs.
While the mechanisms of action of many
therapeutic agents for cancer remain unknown, understanding how an agent works is
an important step in including a therapy in rational combinations, and also in
fully appreciating its potential. Lenalidomide is one such agent that we know
for certain is effective for the treatment of a host of hematologic
malignancies, and yet our understanding of its mechanism(s) of action is quite
limited. This study, therefore, is important to the field in that it directs
other researchers to pursue further the ability of members of this class of
drug to enhance cell membrane-based signaling and activation of RhoA along with
related family members.
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