By Steven Grant, MD
2008-11-01
Dr. Grant indicated no relevant conflicts of interest.
Hassane DC, Guzman ML, Corbett C, et al. Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. Blood. 2008;111:5654-62.
In recent years, targeting cancer stem cells (CSCs) has become the
focus of intense interest in diverse malignancies, including those of
hematopoietic origin, and particularly AML. CSCs are capable of
continuous regeneration and, as a consequence, may serve as an
unlimited reservoir to restore the bulk population of cells following
ablation (e.g., by chemotherapy). Significantly, AML stem cells appear
to be relatively resistant to conventional cytotoxic agents, such as
ara-C or daunorubicin, which very effectively kill bulk populations of
AML blasts, raising the possibility that failure to eradicate AML stem
cells (AML SCs) may be responsible for or contribute to treatment
failure in this disease. On the other hand, evidence has emerged that
certain targeted agents, particularly inhibitors of the NF-κB pathway,
may be particularly effective in eliminating AML SCs.1
One such agent, the sesquiterpene lactone parthenolide, has been shown
to induce AML SC death in association with NF-κB inactivation and
induction of oxidative injury.2 Such findings have prompted efforts to identify other compounds with similar characteristics.
In a recent study, Hassane, et al. describe a novel genetic approach
specifically designed to achieve this aim. Using the
multi-institutional Gene Expression Omnibus (GEO) as a platform, they
hypothesized that compounds capable of eradicating AML SCs would
exhibit a gene profile array similar to that of parthenolide. In silico
screening of this public database by two separate search procedures
yielded two compounds, celastrol and 4-hydroxy-2-nonenal (HNE), whose
signatures mimicked that of parthenolide. Interestingly, both of these
terpenoid compounds shared with parthenolide the ability to ablate the
bulk, progenitor, and SC populations of leukemic cells, disrupt NF-κB
signaling, and induce oxidative stress. The authors concluded that
mining of large, public, gene array databases may provide an extremely
valuable resource for drug discovery by helping to classify both new
and old drugs according to the genetic perturbations that they produce.
More specifically, in the case of AML, such computational tools may
help in identifying the relatively small subset of agents likely to be
effective against the AML SC, rather than the bulk population of blasts.
While the concept of employing sophisticated
computational methods in conjunction with large genetic databases to
discover new agents is clearly an exciting one, the ultimate success of
this strategy in the context of AML will depend upon multiple factors.
First, while it seems intuitive that agents capable of ablating both
AML SC and bulk populations should prove superior to agents that only
ablate bulk populations, this hypothesis has not yet been formally
tested. In this regard, the entry of the parthenolide analog LC-1 into
the clinical arena, including studies involving AML, should begin to
address this question. The possibility also exists that targeting
specific genetic signatures may primarily yield agents mimicking the
pharmacodynamic properties of the index compound. Nevertheless, the
novel drug discovery approach described here clearly has tremendous
potential, and its validation over the years to come is awaited with
great interest.
References
- Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci USA. 2002;99:16220-5.
- Guzman ML, Rossi RM, Karnischky L, et al. The
sesquiterpene lactone parthenolide induces apoptosis of human acute
myelogenous leukemia stem and progenitor cells. Blood. 2005;105:4163-9.
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