Biomedical Engineering Reference
In-Depth Information
the quiescent CML stem cell population (Strauss et al. 2007). Both these
combination strategies require further evaluation, but represent realistic
potential therapeutic options for the cure of CML in the future.
6 Future Challenges in Targeting LSCs
It is becoming increasingly apparent that the development of agents which
specifically target cancer stem cells is vital for the eradication of leukemia and
other stem cell-derived malignancies. It is only by understanding the biology of
cancer stem cells and developing novel stem cell-directed therapies that progress
will be made in eradicating these diseases. At present, a number of pre-clinical
strategies are being pursued to target the quiescent LSC. These include the use
of self-renewal pathway small-molecule inhibitors, proteasome inhibitors,
rapamycin, telomerase inhibitors, 5-azacytidine, HDAC inhibitors, and BMS-
214662. In addition, new potential targets and novel small-molecule inhibitors
are emerging all the time.
It is likely that a successful strategy for eradicating leukemia will consist of
standard chemotherapy agents (e.g., anthracyclines, cytosine arabinoside, flu-
darabine) to kill the majority of leukemia blast cells in combination with a
targeted LSC therapy. The timing of such therapy is likely to be critical and will
require careful planning for successful clinical trials. One potential approach
would be induction chemotherapy with a combination of standard chemother-
apy agents to reduce overall tumor load, followed by LSC-directed therapy
when tumor burden is low to eradicate the quiescent LSC population (Fig. 3).
For such an approach to be successful, LSC-specific markers must be identified
(e.g., CD96 in AML) and sensitive, validated tests (e.g., quantitative RT-PCR
for BCR-ABL in CML) must be available to monitor MRD. However, as
demonstrated with CML, even the most sensitive molecular tests currently
Conventional
chemotherapy
Stem cell directed
therapy
Debulking tumor
mass
Eradication of
disease
LSCs only
LSCs, clonogenic
leukemia cells and
leukemia blast cells
Fig. 3 Schematic diagram of a potential therapeutic strategy to eradicate LSCs. Conventional
chemotherapy agents are used for eliminating the bulk of the clonogenic leukemia progenitor
cells and non-clonogenic leukemia blast cells. This is followed by a LSC-directed therapy to
eradicate the LSC population, which is resistant to conventional chemotherapy, and cure
leukemia
